Bridged polycyclic compound based compositions for topical applications for pets

ABSTRACT

A pharmaceutically active agent, a pharmaceutically active agent carrier and method of use thereof are described. In some embodiments, a system may include a composition. The composition may include one or more bridged polycyclic compounds. At least one of the bridged polycyclic compounds may include at least two cyclic groups, and at least two pharmaceutically active agents may be associated with the bridged polycyclic compound. In some embodiments, one or more bridged polycyclic compounds may be applied to an topical surface and/or an otic surface of an animal (e.g., canine, feline) such that an topical malady and/or otic malady may be inhibited and/or ameliorated.

PRIORITY CLAIM

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/964,312 entitled “BRIDGED POLYCYCLIC COMPOUND BASED COMPOSITIONSFOR COATING SURFACES” filed on Aug. 10, 2007, U.S. Provisional PatentApplication No. 60/965,154 entitled “BRIDGED POLYCYCLIC POLYMER BASEDCOMPOSITIONS FOR THE INHIBITION AND AMELIORATION OF DISEASE” filed onAug. 17, 2007, U.S. Provisional Patent Application No. 61/029,332entitled “BRIDGED POLYCYCLIC COMPOUND BASED COMPOSITIONS FOR COATINGSURFACES” filed on Feb. 16, 2008, and U.S. Provisional PatentApplication No. 61/074,480 entitled “BRIDGED POLYCYCLIC COMPOUND BASEDCOMPOSITIONS FOR TOPICAL APPLICATIONS FOR PETS” filed on Jun. 20, 2008,all of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present disclosure generally relates to bridged polycyclic basedcompounds for the inhibition and amelioration of disease. Moreparticularly, the disclosure generally relates to systems and methodsfor formulating antiviral, antibacterial, antifungal, antidiseasecompositions using these bridged polycyclic based compounds forapplication to topical and otic surfaces.

2. Description of the Relevant Art

Dendrimers are branched polymers with densely packed end-functionalgroups that can be used to attach the dendrimers to bioactive moleculessuch as drugs, targeting ligands and imaging agents. Since a significantportion of a dose of pharmaceutical drugs is lost in the circulation dueto impaired uptake by the cells especially in the case of drug resistantcells. The actual concentration of a drug inside the cells is much lessthan what is present extracellularly. Hence, to accomplish highlyeffective treatment of diseases it is important to increase theintracellular amount of the drug. Dendrimers have already been used as acarrier agent for several known antiviral agents. Attaching these knownagents to a dendrimer has been shown to increase the activity of theagent verses using the agent alone and uncoupled to a dendrimer.However, there are problems associated with using dendrimers, especiallywhen scaling up production to commercial quantities.

Two main methods exist for the synthesis of dendrimers: a divergentapproach, where the dendrimer is assembled in a totally linear manner ora convergent method where fragments of the dendrimer are condensedtogether. These two methods both suffer from major problems when itcomes to practical synthesis, in particular, the necessity for repeatedand time-consuming purifications.

Additional problems associated with the synthesis of dendrimers are:defects in the molecular structure; and the molecular structure ofdendrimers is so crowded that many times other molecules become trappedwithin the spaces within the molecular structure of the dendrimer

Therefore there is a need for a pharmaceutical composition comprising acompound which increases the intracellular amount of pharmaceuticaldrugs but which is easier and cheaper to synthesize than dendrimers andwhich are capable of attaching different functionalities more easily.

A common problem among animals are topical skin infections. Many timesthese infections may be commonly found in and/or around an animals feet.In general these types of foot maladies are referred to aspododermatitis. Pododermatitis is generally an inflammation of the feetof animals.

Many times it is difficult to determine the cause of pododermatitis.Even if a cause is determined, treatment of pododermatitis is oftenproblematic due to reoccurrences or lack of affordable treatmentoptions. In many cases, pododermatitis can only be managed and cannot becured. In some cases surgery, including amputation of all or a portionof the infected animal's foot, may be the only option.

Unless surgery is indicated, pets may be cared for at home in somecases. It may be necessary for an owner to apply foot soaks, hotpacking, and/or bandaging on a daily basis for months at a time.Pharmaceutical therapy may include long-term antibiotics, anti-fungals,steroids, chemotherapeutic agents (cancer), anti-parasitic agents and/orhormone replacement. The pharmaceutical therapy selected will dependupon the underlying cause. Currently systemic, expensive antibiotics areused for this purpose. They don't work well as the infection is usuallya fungus and bacteria combined. Antibiotics treat bacterial infections.

What is needed therefore is an easy to use, effective system formaintaining good skin health, especially in and around an animal's feet(e.g., toes, nails, skin, hooves). What are needed are effective methodsand compositions for preventing and treating topical disease in animals.Preferably such methods and compositions should be easy-to-use andcomprise antimicrobial agents. Such methods and compositions shouldprovide long-term effectiveness against foot problems. Such methods andcompositions should be affordable, safe and easy to use on a regularbasis.

SUMMARY

Embodiments of the present invention address the problems describedabove by providing novel compositions and methods for topicalapplication for reducing and/or ameliorating maladies associated with ananimal's skin and especially their feet, as well as, reducing and/orameliorating maladies associated with an animal's an otic cavity.Embodiments of the present invention provide unique methods andcompositions that are safe and effective for regular use by animals.

In some embodiments, a chemical composition may include a chemicalcompound. The chemical compound may include one or more bridgedpolycyclic compounds. At least one of the bridged polycyclic compoundsmay include at least two cyclic groups. At least two pharmaceuticallyactive agents and/or derivatives of pharmaceutically active agents maybe coupled to the bridged polycyclic compound.

In some embodiments, at least one of the pharmaceutically active agentsmay include an anti-inflammatory agent and/or an antimicrobial agent.

In some embodiments, a chemical composition may include a chemicalcompound, wherein the chemical compound has a general structure (Ia):

Each R¹ may be independently an alkyl group, a substituted alkyl group,an aryl group, a substituted aryl group, N, N⁺H, N⁺R³, a heterocyclegroup, or a substituted heterocycle group. Each R² may be independentlyan alkyl group, a substituted alkyl group, an aryl group, a substitutedaryl group, a heterocycle group, a substituted heterocycle group, acovalent bond, or an alkene. Each R³ may be independently a hydrogen,pharmaceutically active agent, an ester, an alkyl group, a substitutedalkyl group, an aryl group, a substituted aryl group, a heterocyclegroup, a substituted heterocycle group, an alkene, an ether, an ester, aPEG, an amide, an amine, a guanidine, or a PEI. Each R⁴ may beindependently an alkyl group, a substituted alkyl group, an aryl group,a substituted aryl group, a heterocycle group, a substituted heterocyclegroup, an ether, an amide, an alcohol, an ester, a sulfonamide, asulfanilamide, or an alkene. Z may include at least one bridge. At leastone of the bridges may be —R²—N⁺R³ ₂—R⁴—N⁺R³ ₂—R²—, —R²—NR³—R⁴—N⁺R³₂—R²—, —R²—NR³—R⁴—NR³—R²—, or —R²—N═N—R⁴═N═R²—. Each bridge mayindependently couple R¹ to R¹. The chemical compound may include one ormore negatively charged counter ions.

In some embodiments, a bridged polycyclic compound may include a salt ofcompound Ia.

In some embodiments, a chemical composition may include a chemicalcompound, wherein the chemical compound has a general structure:

Z may include

In some embodiments, Z may include at least two bridges.In some embodiments, a chemical composition may include a chemicalcompound, wherein the chemical compound has a general structure:

Z may include

In some embodiments, R³ may include a guanidine moiety, a guanidinederivative and/or a halogenated aryl moiety. R³ may include any of theother moieties associated with R³ herein.

In some embodiments, a chemical compound is a salt of the chemicalcompound. At least one counterion forming the salt may include anacetate ion.

In some embodiments, Y may include a halogen.

In some embodiments, a chemical composition may include a polymer or aprepolymer. At least one polymer is poly(vinyl acetate-co-crotonicacid).

In some embodiments, a z may represent a charge on the chemical compoundand an appropriate number of counterions. z may range from 1-16, 2-14,6-14, or 8-14.

In some embodiments, y may represent a number of bridges coupling theNitrogens of the chemical compound. y may range from 3-8, 3-5, or 3-4.

In some embodiments, n may range from 1-8, 1-4, 2-4, or 1-3. n may be atleast 2.

In some embodiments, a chemical composition may include at least onesolvent.

In some embodiments, a chemical composition may include water and/or analcohol (e.g., ethanol).

In some embodiments, a chemical composition may include apharmaceutically acceptable viscous liquid (e.g., glycerin).

In some embodiments, a protective coating composition may include acompound. A compound may include a bridged polycyclic compound. Abridged polycyclic compound may be a cavitand. Portions of the bridgedpolycyclic compound may include two or more quaternary ammoniummoieties. The coating composition may be antimicrobial.

In some embodiments, a protective coating composition may beantimicrobial.

In some embodiments, a compound may include a shape with a substantiallycurved surface.

In some embodiments, a coating may inhibit microbial adhesion.

In some embodiments, a compound may have a minimum inhibitoryconcentration of less than 0.1 mg/mL.

In some embodiments, a composition may have a minimum inhibitoryconcentration of less than 0.05 mg/mL.

In some embodiments, at least one R¹ is N⁺R³. In some embodiments, atleast one R¹ is

In some embodiments, at least one R³ is hydrophilic. In someembodiments, at least one R³ is a polymer. In some embodiments, at leastone R³ is an oxazoline polymer. In some embodiments, at least one R³ ishydrophobic.

In some embodiments, at least one R⁴ may be

In some embodiments, a composition may include at least one metal (M)coordinated to at least a portion of the compound. At least one M mayinclude a cation. At least one M may be positioned inside a spacedefined by R² and R⁴, and wherein at least one M is coordinated to oneor more N⁺R³ ₂'s.

In some embodiments, at least one X may include a halogen ion.

In some embodiments, at least one X may include one or more elementswith antimicrobial activity.

In some embodiments, at least one X may include one or more elementswith anti-inflammatory activity.

In some embodiments, at least one X may include boron.

In some embodiments, a composition may include one or more metals and/ormetal ions with antimicrobial properties.

In some embodiments, a composition may include one or more metals and/ormetal ions with anti-inflammatory properties.

In some embodiments, at least a portion of a chemical composition mayform an antimicrobial coating over at least a portion of a surface. Thechemical composition may include one or more bridged polycycliccompounds. At least one of the bridged polycyclic compounds may includeat least two cyclic groups.

In some embodiments, a compound and/or a composition may have a minimuminhibitory concentration of greater than 900 μM (e.g., 900 μM-1500 μM,900 μM-2000 μM, 1500 μM-2500 μM, etc.). In some embodiments, a compoundand/or a coating composition may have a minimum inhibitory concentrationof less than 10.0 mg/mL, less than 5.0 mg/mL, less than 1.0 mg/mL, lessthan 0.1 mg/mL, or less than 0.05 mg/mL. In such compositions,antimicrobial properties may not be the primary function of a coatingcomposition.

In some embodiments, a method of coating a surface may include coatingan otic surface.

In some embodiments, a method of coating a surface may include coating adermal surface.

In some embodiments, a method of coating a topical surface may includeapplying a composition to a surface of a topical surface. Thecomposition may include one or more bridged polycyclic compounds. Atleast one of the bridged polycyclic compounds may include at least twocyclic groups. The method may include forming an antimicrobial coatingover at least a portion of the surface.

The topical surface may include at least a portion of a foot surface, atleast a portion of a nail, at least a portion of soft tissue, or atleast a portion of a hoof.

The composition may be in the form of a gel, a foam, a sealant, avarnish, a resin, and/or a coating.

In some embodiments, a composition may include a coalescing solvent.

The method may include using the composition as a bonding agent.

The method may include using the composition as a resin cement.

The method may include using the composition as a sealant.

The method may include using the composition as a varnish.

The method may include using the composition as a resin.

In some embodiments, a topical surface may be coated with a coating. Thecoating may include a chemical composition at least a portion of whichforms an antimicrobial coating over at least a portion of the topicalsurface. The coating may include a chemical composition at least aportion of which forms an antiinflammatory coating over at least aportion of the topical surface. The coating may include a chemicalcomposition at least a portion of which decreases bleeding over at leasta portion of the topical surface. The coating may include a chemicalcomposition at least a portion of which decreases inflammation over atleast a portion of the topical surface. The coating may include achemical composition at least a portion of decreases bacterial, viraland/or fungal infection over at least a portion of the topical surface.The coating may include a chemical composition at least a portion ofwhich decreases infection over at least a portion of the topicalsurface. The chemical composition may include one or more bridgedpolycyclic compounds. At least one of the bridged polycyclic compoundsmay include at least two cyclic groups. At least two cyclic groups maybe defined in part by quaternary ammonium moieties.

In some embodiments, a method of inhibiting or ameliorating a diseasemay include administering to a subject an effective amount of apharmaceutically acceptable formulation comprising a chemicalcomposition as described herein.

In some embodiments, a subject may include a mammal (e.g., canine,feline).

In some embodiments, a method may include administering at least twodifferent pharmaceutically active agents. The agents may be coupled tothe same and/or different bridged polycyclic compounds.

In some embodiments, a chemical compound may decompose during use,wherein one or more of the products of the decomposition may be morebiologically active relative to the chemical compound.

In some embodiments, a method may include administering thepharmaceutically acceptable formulation to a subject in the form of anemulsion.

BRIEF DESCRIPTION OF THE DRAWINGS

Advantages of the present invention may become apparent to those skilledin the art with the benefit of the following detailed description of thepreferred embodiments and upon reference to the accompanying drawings inwhich:

FIG. 1 depicts a graphical representation of time kill assay tests for abridged polycyclic compound tested against HaemophilusActinomycetemcomitans.

FIG. 2 depicts a graphical representation of time kill assay tests for abridged polycyclic compound tested against Streptococcus mutans.

FIG. 3 depicts a graphical representation of time kill assay tests for abridged polycyclic compound tested against Porphymonas Gingivalis.

While the invention is susceptible to various modifications andalternative forms, specific embodiments thereof are shown by way ofexample in the drawings and may herein be described in detail. Thedrawings may not be to scale. It should be understood, however, that thedrawings and detailed description thereto are not intended to limit theinvention to the particular form disclosed, but on the contrary, theintention is to cover all modifications, equivalents and alternativesfalling within the spirit and scope of the present invention as definedby the appended claims.

DETAILED DESCRIPTION

It is to be understood the present invention is not limited toparticular devices or biological systems, which may, of course, vary. Itis also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting. As used in this specification and the appended claims,the singular forms “a”, “an”, and “the” include singular and pluralreferents unless the content clearly dictates otherwise. Thus, forexample, reference to “a linker” includes one or more linkers.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art.

The term “accelerator” as used herein generally refers to a substancethat speeds a chemical reaction.

The term “acyl” as used herein generally refers to a carbonylsubstituent, —C(O)R, where R is alkyl or substituted alkyl, aryl, orsubstituted aryl, which may be called an alkanoyl substituent when R isalkyl.

The terms “administration,” “administering,” or the like, as used hereinwhen used in the context of providing a pharmaceutical, cosmeceutical ornutraceutical composition to a subject generally refers to providing tothe subject one or more pharmaceutical, “over-the-counter” (OTC) ornutraceutical compositions in combination with an appropriate deliveryvehicle by any means such that the administered compound achieves one ormore of the intended biological effects for which the compound wasadministered. By way of non-limiting example, a composition may beadministered parenteral, subcutaneous, intravenous, intracoronary,rectal, intramuscular, intra-peritoneal, transdermal, or buccal routesof delivery. Alternatively, or concurrently, administration may be bythe oral route. The dosage administered will be dependent upon the age,health, weight, and/or disease state of the recipient, kind ofconcurrent treatment, if any, frequency of treatment, and/or the natureof the effect desired. The dosage of pharmacologically active compoundthat is administered will be dependent upon multiple factors, such asthe age, health, weight, and/or disease state of the recipient,concurrent treatments, if any, the frequency of treatment, and/or thenature and magnitude of the biological effect that is desired.

The term “aldehyde” as used herein generally refers to any of a class oforganic compounds containing the group —CHO

The term “aldehyde forming moiety” as used herein generally refers toany of a class of organic compounds which form an aldehyde in solutionor react in an equivalent manner to an aldehyde such that an at leastsimilar chemical product is achieved as would have been achieved with analdehyde.

The terms “alkenyl” and “alkene” as used herein generally refer to anystructure or moiety having the unsaturation C═C. As used herein, theterm “alkynyl” generally refers to any structure or moiety having theunsaturation C≡C.

The term “alkoxy” generally refers to an —OR group, where R is an alkyl,substituted lower alkyl, aryl, substituted aryl. Alkoxy groups include,for example, methoxy, ethoxy, phenoxy, substituted phenoxy, benzyloxy,phenethyloxy, t-butoxy, and others.

The term “alkyl” as used herein generally refers to a chemicalsubstituent containing the monovalent group C_(n)H_(2n), where n is aninteger greater than zero. Alkyl includes a branched or unbranchedmonovalent hydrocarbon radical. An “n-mC” alkyl or “(nC-mC)alkyl” refersto all alkyl groups containing from n to m carbon atoms. For example, a1-4C alkyl refers to a methyl, ethyl, propyl, or butyl group. Allpossible isomers of an indicated alkyl are also included. Thus, propylincludes isopropyl, butyl includes n-butyl, isobutyl and t-butyl, and soon. The term alkyl may include substituted alkyls.

The term “alkyl-aryl” as used herein generally refers to a chemicalsubstituent containing an alkyl group coupled to an aryl group or asubstituted aryl group.

The terms “amino” or “amine” as used herein generally refer to a group—NRR′, where R and R′ may independently include, but are not limited to,hydrogen, alkyl, substituted alkyl, aryl, substituted aryl or acyl.Amine or amino may include a salt of the amine group.

The terms “amine forming moiety” as used herein generally refers to anyof a class of organic compounds which form an amine in solution or reactin an equivalent manner to an amine such that an at least similarchemical product is achieved as would have been achieved with an amine.

The terms “amphiphile” or “amphiphilic” as used herein generally referto a molecule or species which exhibits both hydrophilic and lipophiliccharacter. In general, an amphiphile contains a lipophilic moiety and ahydrophilic moiety. The terms “lipophilic” and “hydrophobic” areinterchangeable as used herein. An amphiphile may form a Langmuir film.

Non-limiting examples of hydrophobic groups or moieties include loweralkyl groups, alkyl groups having 6, 7, 8, 9, 10, 11, 12, or more carbonatoms, including alkyl groups with 14-30, or 30 or more carbon atoms,substituted alkyl groups, alkenyl groups, alkynyl groups, aryl groups,substituted aryl groups, saturated or unsaturated cyclic hydrocarbons,heteroaryl, heteroarylalkyl, heterocyclic, and corresponding substitutedgroups. A hydrophobic group may contain some hydrophilic groups orsubstituents insofar as the hydrophobic character of the group is notoutweighed. In further variations, a hydrophobic group may includesubstituted silicon atoms, and may include fluorine atoms. Thehydrophobic moieties may be linear, branched, or cyclic.

Non-limiting examples of hydrophilic groups or moieties includehydroxyl, methoxy, phenyl, carboxylic acids and salts thereof, methyl,ethyl, and vinyl esters of carboxylic acids, amides, amino, cyano,isocyano, nitrile, ammonium salts, sulfonium salts, phosphonium salts,mono- and di-alkyl substituted amino groups, polypropyleneglycols,polyethylene glycols, glycosyl groups, sugars, epoxy groups, acrylates,sulfonamides, nitro, —OP(O)(OCH₂CH₂N⁺RRR)O⁻, guanidinium, aminate,acrylamide, pyridinium, piperidine, and combinations thereof, whereineach R is independently selected from H or alkyl. Further examplesinclude polymethylene chains substituted with alcohol, carboxylate,acrylate, or methacrylate. Hydrophilic moieties may also include alkylchains having internal amino or substituted amino groups, for example,internal —NH—, —NC(O)R—, or —NC(O)CH═CH₂— groups, wherein R is H oralkyl. Hydrophilic moieties may also include polycaprolactones,polycaprolactone diols, poly(acetic acid)s, poly(vinyl acetates)s,poly(2-vinyl pyridine)s, cellulose esters, cellulose hydroxylethers,poly(L-lysine hydrobromide)s, poly(itaconic acid)s, poly(maleic acid)s,poly(styrenesulfonic acid)s, poly(aniline)s, or poly(vinyl phosphonicacid)s. A hydrophilic group may contain some hydrophobic groups orsubstituents insofar as the hydrophilic character of the group is notoutweighed.

The term “animal” as used herein generally refers to any member of thekingdom Animalia, comprising multicellular organisms that have awell-defined shape and usually limited growth, can move voluntarily,actively acquire food and digest it internally, and have sensory andnervous systems that allow them to respond rapidly to stimuli: someclassification schemes also include protozoa and certain othersingle-celled eukaryotes that have motility and animal like nutritionalmodes. Generally the term animal as used herein does not refer tohumans.

The term “antiinflammatory” as used herein generally refers to asubstance acting to reduce certain signs of inflammation (e.g.,swelling, tenderness, fever, and pain).

The term “antimicrobial” as used herein generally refers to a substancecapable of destroying or inhibiting the growth of microbes, prevents thedevelopment of microbes, and/or inhibits the pathogenic action ofmicrobes as well as viruses, fungi, and bacteria.

The term “aryl” as used herein generally refers to a chemicalsubstituent containing an aromatic group (e.g., phenyl). An aromaticgroup may be a single aromatic ring or multiple aromatic rings which arefused together, coupled covalently, or coupled to a common group such asa methylene, ethylene, or carbonyl, and includes polynuclear ringstructures. An aromatic ring or rings may include, but is not limitedto, substituted or unsubstituted phenyl, naphthyl, biphenyl,diphenylmethyl, and benzophenone groups. The term “aryl” includessubstituted aryls

The term “avian” as used herein generally refers to any of thebiological family Aves including a class of vertebrates comprising thebirds. Aves are generally characterized by have a complete doublecirculation, oviparous, reproduction, front limbs peculiarly modified aswings; and they bear feathers. All existing birds have a horny beak,without teeth.

The term “bridged polycyclic compound” as used herein generally refersto a compound that is composed of two or more cyclic systems that sharetwo or more atoms. A cyclic system is formed from a group of atoms whichtogether form a continuous loop. A bridged polycyclic compound mayinclude a bridging atom or group of atoms that connects two or morenon-adjacent positions of the same ring. An example of a bridgedbicyclic system (i.e., a compound composed of two cyclic systems) withtwo atoms (atoms “A”) common to both cyclic systems is depicted below.One of the linking groups “L” represents a bridging atom or group ofatoms.

The term “building substrate” as used herein generally refers to anatural or synthetic material used in the construction of a residentialor commercial structure.

The term “canine” as used herein generally refers to any of thebiological family Canidae including carnivorous mammals includingwolves, jackals, foxes, coyote, and the domestic dog.

The term “cavitand” as used herein generally refers to a natural orsynthetic molecular compound with enforced cavities large enough tocomplex complementary compounds or ions. More specifically, a cavitandmay be generally defined as a three-dimensional compound that maintainsa substantially rigid structure and binds a variety of molecules in thecavities produced by the structure of the three-dimensional compound.

The term “chelating agent or complexing agent” as used herein generallyrefers to any of various compounds that combine with metals to formchelates.

The term “coalescing agents or solvents” as used herein generally refersto any of various compounds that are used in coatings to promote filmformation (e.g., in architectural and industrial latex coating).

The terms “coupling” and “coupled” with respect to molecular moieties orspecies, atoms, synthons, cyclic compounds, and nanoparticles refers totheir attachment or association with other molecular moieties orspecies, atoms, synthons, cyclic compounds, and nanoparticles. Theattachment or association may be specific or non-specific, reversible ornon-reversible, the result of chemical reaction, or complexation orcharge transfer. The bonds formed by a coupling reaction are oftencovalent bonds, or polar-covalent bonds, or mixed ionic-covalent bonds,and may sometimes be Coulombic forces, ionic or electrostatic forces orinteractions.

The terms “crystalline” or “substantially crystalline”, when used withrespect to nanostructures, refer to the fact that the nanostructurestypically exhibit long-range ordering across one or more dimensions ofthe structure. It will be understood by one of skill in the art that theterm “long range ordering” will depend on the absolute size of thespecific nanostructures, as ordering for a single crystal typically doesnot extend beyond the boundaries of the crystal. In this case,“long-range ordering” will mean substantial order across at least themajority of the dimension of the nanostructure. In some instances, ananostructure may bear an oxide or other coating, or may be comprised ofa core and at least one shell. In such instances it will be appreciatedthat the oxide, shell(s), or other coating need not exhibit suchordering (e.g., it may be amorphous, polycrystalline, or otherwise). Insuch instances, the phrase “crystalline,” “substantially crystalline,”“substantially monocrystalline,” or “monocrystalline” refers to thecentral core of the nanostructure (excluding the coating layers orshells). The terms “crystalline” or “substantially crystalline” as usedherein are intended to also encompass structures comprising variousdefects, stacking faults, atomic substitutions, etc., as long as thestructure exhibits substantial long range ordering (e.g., order over atleast about 80% of the length of at least one axis of the nanostructureor its core). It may be appreciated that the interface between a coreand the outside of a nanostructure or between a core and an adjacentshell or between a shell and a second adjacent shell may containnon-crystalline regions and may even be amorphous. This does not preventthe nanostructure from being crystalline or substantially crystalline asdefined herein.

The term “cyclic” as used herein generally refers to compounds havingwherein at least some of the atoms are arranged in a ring orclosed-chain structure.

The term “disease” as used herein generally refers to a disordered orincorrectly functioning organ, part, structure, or system of the bodyresulting from the effect of genetic or developmental errors, infection,poisons, nutritional deficiency or imbalance, toxicity, or unfavorableenvironmental factors; illness; sickness; ailment.

The terms “effective concentration” or “effective amount” as used hereingenerally refers to a sufficient amount of the pharmaceutically activeagent is added to decrease, prevent or inhibit the growth of a virusand/or cancerous growth. The amount will vary for each compound and uponknown factors related to the item or use to which the pharmaceuticallyactive agent is applied.

The phrase “enteric coating” as used herein generally refers to abarrier applied to oral medication that controls the location in thedigestive system where it is absorbed. Enteric refers to the smallintestine, therefore enteric coatings prevent release of medicationbefore it reaches the small intestine. Most enteric coatings work bypresenting a surface that is stable at the highly acidic pH found in thestomach, but breaks down rapidly at a less acidic (relatively morebasic) pH. For example, they will not dissolve in the acidic juices ofthe stomach (pH˜3), but they will in the higher pH (above pH 5.5)environment present in the small intestine.

The term “feline” as used herein generally refers to any of thebiological family Felidae including lithe-bodied carnivorous mammals (asthe lion, lynx, and cheetah, as well as the common house cat) havingoften strikingly patterned fur, comparatively short limbs with soft padson the feet, usually sharp curved retractile claws, a broad and somewhatrounded head with short but powerful jaws equipped with teeth suited tograsping, tearing, and shearing through flesh, erect ears, and typicallyeyes with narrow or elliptical pupils and especially adapted for seeingin dim light.

The terms “functionalized” or “functional group” as used hereingenerally refers to the presence of a reactive chemical moiety orfunctionality. A functional group may include, but is not limited to,chemical groups, biochemical groups, organic groups, inorganic groups,organometallic groups, aryl groups, heteroaryl groups, cyclichydrocarbon groups, amino (—NH₂), hydroxyl (—OH), cyano (—C≡N), nitro(NO₂), carboxyl (—COOH), formyl (—CHO), keto (—CH₂C(O)CH₂—), ether(—CH₂—O—CH₂—), thioether (—CH₂—S—CH₂—), alkenyl (—C═C—), alkynyl,(—C≡C—), epoxy

metalloids (functionality containing Si and/or B) and halo (F, Cl, Br,and I) groups. In some embodiments, the functional group is an organicgroup.

The term “gram-negative bacteria” or “gram-negative bacterium” as usedherein generally refers to bacteria which have been classified by theGram stain as having a red stain. Gram-negative bacteria have thinwalled cell membranes consisting of a single layer of peptidoglycan andan outer layer of lipopolysacchacide, lipoprotein, and phospholipid.Exemplary organisms include, but are not limited to, Enterobacteriaceaconsisting of Escherichia, Shigella, Edwardsiella, Salmonella,Citrobacter, Klebsiella, Enterobacter, Hafnia, Serratia, Proteus,Morganella, Providencia, Yersinia, Erwinia, Buttlauxella, Cedecea,Ewingella, Kluyvera, Tatumella and Rahnella. Other exemplarygram-negative organisms not in the family Enterobacteriacea include, butare not limited to, Pseudomonas aeruginosa, Stenotrophomonasmaltophilia, Burkholderia, Cepacia, Gardenerella, Vaginalis, andAcinetobacter species.

The term “gram-positive bacteria” or “gram-positive bacterium” as usedherein generally refers to bacteria, which have been classified usingthe Gram stain as having a blue stain. Gram-positive bacteria have athick cell membrane consisting of multiple layers of peptidoglycan andan outside layer of teichoic acid. Exemplary organisms include, but arenot limited to, Staphylococcus aureus, coagulase-negative staphylococci,streptococci, enterococci, corynebacteria, and Bacillus species.

The term “guanidine” as used herein generally refers to

Guanidine may also refer to derivatives of guanidine

including, for example, salts of guanidine.

The term “heteroaryl” generally refers to a completely unsaturatedheterocycle.

The term “heterocycle” as used herein generally refers to a closed-ringstructure, in which one or more of the atoms in the ring is an elementother than carbon. Heterocycle may include aromatic compounds ornon-aromatic compounds. Heterocycles may include rings such asthiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan, orbenzo-fused analogues of these rings. Examples of heterocycles includetetrahydrofuran, morpholine, piperidine, pyrrolidine, and others. Insome embodiments, “heterocycle” is intended to mean a stable 5- to7-membered monocyclic or bicyclic or 7- to 10-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from 1 to 4 heteroatoms (e.g., N, O, and S)and wherein the nitrogen and sulfur heteroatoms may optionally beoxidized, and the nitrogen may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. In some embodiments, heterocycles mayinclude cyclic rings including boron atoms. The heterocyclic ring may beattached to its pendant group at any heteroatom or carbon atom whichresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. Examples of such heterocycles include, but are notlimited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl,2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzofuranyl,benzothiophenyl, carbazole, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl,imidazolyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl),isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl,phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thienyl,thiophenyl, triazinyl, xanthenyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

The term “initiator” as used herein generally refers to a substance thatinitiates a chemical reaction.

The term “ion” as used herein generally refers to an atom(s), radical,or molecule(s) that has lost or gained one or more electrons and hasthus acquired an electric charge.

The terms “in need of treatment” or “in need thereof” when used in thecontext of a subject being administered a pharmacologically activecomposition, generally refers to a judgment made by an appropriatehealthcare provider that an individual or animal requires or willbenefit from a specified treatment or medical intervention. Suchjudgments may be made based on a variety of factors that are in therealm of expertise of healthcare providers, but include knowledge thatthe individual or animal is ill, will be ill, or is at risk of becomingill, as the result of a condition that may be ameliorated or treatedwith the specified medical intervention.

The term “malady” as used herein generally refers to any disorder ordisease of the body or any undesirable or disordered conditionincluding, but not limited to, illness, sickness, affliction, complaint,ailment, indisposition, virus, disease, fungus, infection, disease, etc.

The term “mammal” as used herein generally refers to any vertebrate ofthe class Mammalia, having the body more or less covered with hair,nourishing the young with milk from the mammary glands, and, with theexception of the egg-laying monotremes, giving birth to live young.Generally the term mammal as used herein does not refer to humans.

The term “matrix” generally refers to a material, often a polymericmaterial and/or a prepolymeric material, into which a second material(e.g., a nanostructure) is embedded, surrounded, or otherwiseassociated. A matrix is typically composed of one or more monomers, butmay include other matrix components/constituents. Often the matrixconstituents include one or more “addressable” components orcomplementary binding pairs, that optionally promote assembly and/orcross-linkage of the matrix.

The term “medical device” as used herein generally refers to a deviceused which pertains to treating or determining the state of one'shealth. Medical devices are any article that contacts subjects or areused in health care, and may be for use either internally or externally.

The term “microbe” as used herein generally refers to a minute lifeform; a microorganism. In some embodiments, a microbe may include abacterium that causes disease.

The term “modulate,” as used herein, generally refers to a change or analteration in the magnitude of a be used herein to biological parametersuch as, for example, foci formation, tumorigenic or neoplasticpotential, apoptosis, growth kinetics, expression of one or more genesor proteins of interest, metabolism, oxidative stress, replicativestatus, intercellular communication, or the like. “Modulation” may referto a net increase or a net decrease in the biological parameter.

The term “monocrystalline” when used with respect to a nanostructureindicates that the nanostructure is substantially crystalline andcomprises substantially a single crystal. When used with respect to ananostructure heterostructure comprising a core and one or more shells,“monocrystalline” indicates that the core is substantially crystallineand comprises substantially a single crystal.

The terms “mono functional”, “bifunctional”, “trifunctional”, and“multifunctional” generally refers to a number of attachment sites aparticular compound, molecule, atom, etc. may include (monofunctionalhaving one site, bifunctional having two sites, trifunctional havingthree sites, and multifunctional having more than one site).

The term “nanocrystal” as used herein generally refers to ananostructure that is substantially monocrystalline. A nanocrystal thushas at least one region or characteristic dimension with a dimension ofless than about 500 nm, e.g., less than about 200 nm, less than about100 nm, less than about 50 nm, or even less than about 20 nm. The regionor characteristic dimension may be along the smallest axis of thestructure. Examples of such structures include nanowires, nanorods,nanotubes, branched nanowires, nanotetrapods, nanotripods, nanobipods,nanocrystals, nanodots, quantum dots, nanoparticles, nanoribbons, etc.Nanostructures may be substantially homogeneous in material properties,or in certain embodiments may be heterogeneous (e.g., heterostructures).Optionally, a nanocrystal may comprise one or more surface ligands(e.g., surfactants). The nanocrystal is optionally substantially singlecrystal in structure (a “single crystal nanostructure” or a“monocrystalline nanostructure”). Nanostructures may be fabricated fromessentially any convenient material or material, the nanostructure maybe prepared from an inorganic material, e.g., an inorganic conductive orsemiconductive material. A conductive or semi-conductive nanostructureoften displays 1-dimensional quantum confinement, e.g., an electron mayoften travel along only one dimension of the structure. Nanocrystals maybe substantially homogeneous in material properties, or in certainembodiments may be heterogeneous (e.g., heterostructures). The term“nanocrystal” is intended to encompass substantially monocrystallinenanostructures comprising various defects, stacking faults, atomicsubstitutions, etc., as well as substantially monocrystallinenanostructures without such defects, faults, or substitutions. In thecase of nanocrystal heterostructures comprising a core and one or moreshells, the core of the nanocrystal is typically substantiallymonocrystalline, but the shell(s) need not be. The nanocrystals may befabricated from essentially any convenient material or materials.

The terms “nanostructure” or “nanoparticle” are used herein to generallyrefer to a structure having at least one region or characteristicdimension with a dimension of less than about 500 nm, e.g., less thanabout 200 nm, less than about 100 nm, less than about 50 nm, or evenless than about 20 nm. The region or characteristic dimension may bealong the smallest axis of the structure. Examples of such structuresinclude nanowires, nanorods, nanotubes, branched nanocrystals,nanotetrapods, tripods, bipods, nanocrystals, nanodots, quantum dots,nanoparticles, branched tetrapods (e.g., inorganic dendrimers), etc.Nanostructures may be substantially homogeneous in material properties,or in certain embodiments may be heterogeneous (e.g., heterostructures).Nanostructures may be, e.g., substantially crystalline, substantiallymonocrystalline, polycrystalline, amorphous, or a combination thereof.In one aspect, each of the three dimensions of the nanostructure has adimension of less than about 500 nm, e.g., less than about 200 nm, lessthan about 100 nm, less than about 50 nm, or even less than about 20 nm.Nanostructures may comprise one or more surface ligands (e.g.,surfactants).

The term “nonsystemic” as used herein, generally refers to a compound orcomposition which is not substantially absorbable into the bloodstreamof a human or animal.

The terms “oligomeric” and “polymeric” as used herein are generally usedinterchangeably herein to generally refer to multimeric structureshaving more than one component monomer or subunit.

The term “organ” is used herein to generally refer to a part of the bodyof an animal or of a human generally refers to the collection of cells,tissues, connective tissues, fluids and structures that are part of astructure in an animal or a human that is capable of performing somespecialized physiological function. Groups of organs constitute one ormore specialized body systems. The specialized function performed by anorgan is typically essential to the life or to the overall well-being ofthe animal or human. Non-limiting examples of body organs include theheart, lungs, kidney, ureter, urinary bladder, adrenal glands, pituitarygland, skin, prostate, uterus, reproductive organs (e.g., genitalia andaccessory organs), liver, gall-bladder, brain, spinal cord, stomach,intestine, appendix, pancreas, lymph nodes, breast, salivary glands,lacrimal glands, eyes, spleen, thymus, bone marrow. Non-limitingexamples of body systems include the respiratory, circulatory,cardiovascular, lymphatic, immune, musculoskeletal, nervous, digestive,endocrine, exocrine, hepato-biliary, reproductive, and urinary systems.In animals, the organs are generally made up of several tissues, one ofwhich usually predominates, and determines the principal function of theorgan.

The term “opthalmic” as used herein generally is of or relating to orresembling the eye; “ocular muscles”; “an ocular organ”; “oculardiseases”.

The term “oral surface” as used herein generally refers to a portion ofthe mouth and/or something positioned in and/or coupled to a portion ofthe mouth. For example an oral surface may include, but is not limitedto, at least a portion of a tooth, at least a portion of the gum, atleast a portion of the tongue, at least a portion of a dental fixture(e.g., a filling, a bridge, a cap a false tooth).

The term “otic” as used herein generally refers to tissue in and/oraround an ear, including the otic cavity; auricular.

The term “pharmaceutically acceptable salts” as used herein generallyincludes salts prepared from by reacting pharmaceutically acceptablenon-toxic bases or acids, including inorganic or organic bases, withinorganic or organic acids. Pharmaceutically acceptable salts mayinclude salts derived from inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts,manganous, potassium, sodium, zinc, etc. Examples include the ammonium,calcium, magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-dibenzylethylenediamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, etc.

The term “pharmaceutically active agent” as used herein generally refersto a drug or other substance that has therapeutic value to a livingorganism including without limitation antithrombotics, anticoagulants,antiplatelet agents, thrombolytics, antiproliferatives, antiviral,antitumor, anticancer, antimicrobial, antifungal, anti-inflammatories,agents that inhibit restenosis, smooth muscle cell inhibitors,antibiotics, and the like, and mixtures thereof.

Terms such as “pharmaceutical composition,” “pharmaceuticalformulation,” “pharmaceutical preparation,” or the like, are used hereinto generally refer to formulations that are adapted to deliver aprescribed dosage of one or more pharmacologically active compounds to acell, a group of cells, an organ or tissue, an animal or a human.Methods of incorporating pharmacologically active compounds intopharmaceutical preparations are widely known in the art. Thedetermination of an appropriate prescribed dosage of a pharmacologicallyactive compound to include in a pharmaceutical composition in order toachieve a desired biological outcome is within the skill level of anordinary practitioner of the art. A pharmaceutical composition may beprovided as sustained-release or timed-release formulations. Suchformulations may release a bolus of a compound from the formulation at adesired time, or may ensure a relatively constant amount of the compoundpresent in the dosage is released over a given period of time. Termssuch as “sustained release,” “controlled release,” or “timed release”and the like are widely used in the pharmaceutical arts and are readilyunderstood by a practitioner of ordinary skill in the art.Pharmaceutical preparations may be prepared as solids, semi-solids,gels, hydrogels, liquids, solutions, suspensions, emulsions, aerosols,powders, or combinations thereof. Included in a pharmaceuticalpreparation may be one or more carriers, preservatives, flavorings,excipients, coatings, stabilizers, binders, solvents and/or auxiliariesthat are, typically, pharmacologically inert. It will be readilyappreciated by an ordinary practitioner of the art that, included withinthe meaning of the term are pharmaceutically acceptable salts ofcompounds. It will further be appreciated by an ordinary practitioner ofthe art that the term also encompasses those pharmaceutical compositionsthat contain an admixture of two or more pharmacologically activecompounds, such compounds being administered, for example, as acombination therapy.

A “pharmaceutically or nutraceutically acceptable formulation,” as usedherein, generally refers to a non-toxic formulation containing apredetermined dosage of a pharmaceutical and/or nutraceuticalcomposition, wherein the dosage of the pharmaceutical and/ornutraceutical composition is adequate to achieve a desired biologicaloutcome. The meaning of the term may generally include an appropriatedelivery vehicle that is suitable for properly delivering thepharmaceutical composition in order to achieve the desired biologicaloutcome.

The term “pharmacologically inert,” as used herein, generally refers toa compound, additive, binder, vehicle, and the like, that issubstantially free of any pharmacologic or “drug-like” activity.

The term “polycyclic,” as used herein, generally refers to a chemicalcompound having two or more atomic rings in a molecule. Steroids arepolycyclic compounds.

The term “polymerizable compound,” as used herein, generally refers to achemical compound, substituent or moiety capable of undergoing aself-polymerization and/or co-polymerization reaction (e.g., vinylderivatives, butadienes, trienes, tetraenes, dialkenes, acetylenes,diacetylenes, styrene derivatives).

By “prophylactically effective amount” is meant an amount of apharmaceutical composition that will substantially prevent, delay orreduce the risk of occurrence of the biological or physiological eventin a cell, a tissue, a system, animal or human that is being sought by aresearcher, veterinarian, physician or other caregiver.

The term “quaternary ammonium moiety,” as used herein, generally refersto a tetravalent charged nitrogen (e.g., N⁺R³ ₄).

The terms “R^(n)” in a chemical formula refer to a hydrogen or afunctional group, each independently selected, unless stated otherwise.In some embodiments the functional group may be an organic group. Insome embodiments the functional group may be an alkyl group. In someembodiment, the functional group may be a hydrophobic or hydrophilicgroup.

The terms “reducing,” “inhibiting” and “ameliorating,” as used herein,when used in the context of modulating a pathological or disease state,generally refers to the prevention and/or reduction of at least aportion of the negative consequences of the disease state. When used inthe context of an adverse side effect associated with the administrationof a drug to a subject, the term(s) generally refer to a net reductionin the severity or seriousness of said adverse side effects.

The term “subject” as used herein generally refers to a mammal (e.g.,felines, canines), and in particular to a human.

The term “sealant,” as used herein, generally refers to any of variousliquids, paints, chemicals, or soft substances that may be applied to asurface or circulated through a system of pipes or the like, drying toform a hard, substantially watertight coating.

The term “substituted alkyl” as used herein generally refers to an alkylgroup with an additional group or groups attached to any carbon of thealkyl group. Substituent groups may include one or more functionalgroups such as alkyl, lower alkyl, aryl, acyl, halogen, alkylhalo,hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy,aryloxyalkyl, mercapto, both saturated and unsaturated cyclichydrocarbons, heterocycles, and other organic groups.

The term “substituted alkyl-aryl” as used herein generally refers to analkyl-aryl group with an additional group or groups attached to anycarbon of the alkyl-aryl group. Additional groups may include one ormore functional groups such as lower alkyl, aryl, acyl, halogen,alkylhalo, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy,aryloxy, aryloxyalkyl, thioether, heterocycles, both saturated andunsaturated cyclic hydrocarbons which are fused to the aromatic ring(s),coupled covalently or coupled to a common group such as a methylene orethylene group, or a carbonyl coupling group such as in cyclohexylphenyl ketone, and others.

The term “substituted aryl” as used herein generally refers to an arylgroup with an additional group or groups attached to any carbon of thearyl group. Additional groups may include one or more functional groupssuch as lower alkyl, aryl, acyl, halogen, alkylhalo, hydroxy, amino,alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl,thioether, heterocycles, both saturated and unsaturated cyclichydrocarbons which are fused to the aromatic ring(s), coupled covalentlyor coupled to a common group such as a methylene or ethylene group, or acarbonyl coupling group such as in cyclohexyl phenyl ketone, and others.

The term “substituted heterocycle” as used herein generally refers to aheterocyclic group with an additional group or groups attached to anyelement of the heterocyclic group. Additional groups may include one ormore functional groups such as lower alkyl, aryl, acyl, halogen,alkylhalos, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy,aryloxy, aryloxyalkyl, thioether, heterocycles, both saturated andunsaturated cyclic hydrocarbons which are fused to the heterocyclicring(s), coupled covalently or coupled to a common group such as amethylene or ethylene group, or a carbonyl coupling group such as incyclohexyl phenyl ketone, and others.

The term “substrate” as used herein generally refers to a body or baselayer or material (e.g., onto which other layers are deposited).

The phrase “therapeutically effective amount” generally refers to anamount of a drug or pharmaceutical composition that will elicit at leastone desired biological or physiological response of a cell, a tissue, asystem, animal or human that is being sought by a researcher,veterinarian, physician or other caregiver.

The term “thioether” as used herein generally refers to the generalstructure R—S—R′ in which R and R′ are the same or different and may bealkyl, aryl or heterocyclic groups. The group —SH may also be referredto as “sulfhydryl” or “thiol” or “mercapto.”

As used herein, the term “tissue”, when used in reference to a part of abody or of an organ, generally refers to an aggregation or collection ofmorphologically similar cells and associated accessory and support cellsand intercellular matter, including extracellular matrix material,vascular supply, and fluids, acting together to perform specificfunctions in the body. There are generally four basic types of tissue inanimals and humans including muscle, nerve, epithelial, and connectivetissues.

The term “topical” as used herein generally is of, pertaining to, orapplied externally to a particular part of the body.

The term “virus” as used herein generally refers to an ultramicroscopic(20 to 300 nm in diameter), metabolically inert, infectious agent thatreplicates only within the cells of living hosts, mainly bacteria,plants, and animals: composed of an RNA or DNA core, a protein coat,and, in more complex types, a surrounding envelope.

Bridged Polycyclic Compounds

New antimicrobials are required to combat the new antimicrobialresistant microbes. New antimicrobials may be effective verses microbeswhich are currently resistant to currently known antimicrobials. Newantimicrobials may resist leaching off into the environment beyond apredetermined amount to inhibit polluting the environment unnecessarily(which may concurrently increase the occurrence of antimicrobialresistant microbes from overexposure of antimicrobials).

One strategy for combating antimicrobial resistant organisms is bymodifying known antimicrobials to increase their effectiveness. In someembodiments, quaternary ammonium compounds may be modified to increasetheir effectiveness. It is typically thought that quaternary ammoniumcompounds denature the proteins of the bacterial or fungal cell, affectthe metabolic reactions of the cell and allow vital substances to leakout of the cell, finally causing death. In addition, quaternary ammoniumcompounds are not known to be toxic towards higher forms of life (e.g.,humans).

One of the main considerations in examining the mode of action is thecharacterization of quaternary ammonium compounds as cationicsurfactants. This class of chemical reduces the surface tension atinterfaces, and is attracted to negatively charged surfaces, includingmicroorganisms. Quaternary ammonium compounds denature the proteins ofthe bacterial or fungal cell, affect the metabolic reactions of the celland allow vital substances to leak out of the cell, finally causingdeath.

Most uses of quaternary ammonium compounds as antimicrobials involveformulations of disinfectants and sanitizers which are not bound to asurface, resulting in effluent stream pollution and contamination. Theyare simply wetted onto the surface such as in disinfecting wipes whichare primarily ammonium salts as their liquid active ingredient. Whenthey are incorporated into surfaces they are not crosslinked but areallowed to float to the surface thereby becoming depleted over time thesame way silver and triclosan are incorporated in plastics. Couplingquaternary ammonium compounds to a surface or formation within a polymermatrix may inherently reduce the effectiveness of the quaternaryammonium compounds, by decreasing the accessibility of microbes to themost active cationic portion of the molecule. Increasing accessibilityto the quaternary ammonium compounds within a surface coating or withany use increases the effectiveness of the quaternary ammonium compound.

In some embodiments, the effectiveness of an antimicrobial (e.g.,quaternary ammonium compound) may be increased by coupling theantimicrobial within or on a curved surface, where the curved surface ison a molecular scale. For example, a curved surface may be created usingnanoparticles (e.g., spherical nanoparticles). Nanoparticles mayincorporate into their structure antimicrobial compounds with greaterexposed surface area due to the curved surface of the nanoparticle.

In some embodiments, a compound may include a nanoparticle. Thenanoparticle may include a bridged polycyclic compound. A compound maybe formed using self-assembly techniques and principles. A compound maybe formed from portions which are themselves antimicrobial (e.g.,quaternary ammonium compounds). A compound may bind moieties to at leastportions of itself which have, for example, antimicrobial properties.

In some embodiments, a protective coating composition may include acompound. A compound may be a bridged polycyclic compound. A bridgedpolycyclic compound may be a cavitand. Portions of the bridgedpolycyclic compound may include two or more quaternary ammoniummoieties. The protective coating composition may be antimicrobial.

New carrier agents are required to more effectively deliver existing andfuture pharmaceutical agents.

One strategy for more effectively delivering pharmaceutical agents is tocouple a multitude of pharmaceutical agents (e.g., a single type ofagent or a combination of different agents) to a single molecularentity.

In some embodiments, the effectiveness of a pharmaceutically activeagent may be increased by coupling the agent within or on a curvedsurface, where the curved surface is on a molecular scale. For example,a curved surface may be created using nanoparticles (e.g., sphericalnanoparticles). Nanoparticles may incorporate into their structurepharmaceutically active agent with greater exposed surface area due tothe curved surface of the nanoparticle.

In some embodiments, a pharmaceutically active agent may include usingderivatives of pharmaceutically active agents. Pharmaceutically activeagents may be modified in order to couple the agent to one or morebridged polycyclic compounds. Pharmaceutically active agents may bemodified in order to increase their effectiveness.

In some embodiments, a compound may include a nanoparticle. Thenanoparticle may include a bridged polycyclic compound. A compound maybe formed using self-assembly techniques and principles. A compound maybe formed from portions which are pharmaceutically active agents. Acompound may bind moieties to at least portions of itself which arepharmaceutically active agents.

In some embodiments, a composition may include one or more bridgedpolycyclic compounds. At least one of the bridged polycyclic compoundsmay include at least two cyclic groups. A general example of a bridgedpolycylic compound including only two cyclic groups may include, but isnot limited to, a compound 100 having a general structure

In some embodiments, at least two cyclic groups may be defined in partby quaternary ammonium moieties, by the nitrogen of the quaternaryammonium moiety comprising one of the atoms which forms a part of thecyclic structure itself. For example, a cyclic structure which is formedat least in part by a quaternary ammonium moiety may include, but is notlimited to structure 101

Structure 101 is an example of quaternary ammonium moieties defining atleast in part a cyclic group, however, compound 101 is not an example ofa polycyclic compound and compound 101 is not an example of a bridgedpolycyclic compound.

In some embodiments, a bridged polycyclic compound may include at leasttwo quaternary ammonium moieties, at least three quaternary ammoniummoieties, at least four quaternary ammonium moieties, at least fivequaternary ammonium moieties, at least six quaternary ammonium moieties,at least seven quaternary ammonium moieties, or at least eightquaternary ammonium moieties.

In some embodiments, a compound 100 may have a general structure

Compound 100 may be formed by coupling a trifunctional corner unit Awith a bifunctional linker unit L as depicted in Scheme 2.

Scheme 2 should not be used to limit the disclosure set forth herein.Corner unit A may include multiple dentate linkers other than the onedepicted in Scheme 2 (e.g., a trifunctional linker A is depicted inScheme 2) including, but not limited to, bifunctional, tetrafunctional(e.g., compound 100a) etc. In some embodiments, a corner unit A may becoupled to a linker unit L in any multitude of ways known to one skilledin the art.

In some embodiments, a compound 100c may have a general structure

Compound 100c may be a bridged polycyclic compound. In some embodiments,Z may include at least one bridge. Bridge Z may couple 2 non adjacentatoms.

In some embodiments, at least one of the bridges is —R²—N⁺R³ ₂—R⁴—N⁺R³₂—R²—, such that each bridge independently couples A to A. In someembodiments, at least one of the bridges may be —R²—NR³—R⁴—N⁺R³ ₂—R²—.Each bridge may independently couple A to A. In some embodiments, atleast one of the bridges may be —R²—NR³—R⁴—NR³—R²—. Each bridge mayindependently couple A to A. In some embodiments, at least one of thebridges may be —R²—N═R⁴═N—R²—. Each bridge may independently couple A toA.

For example when Z is 1 compound 100c may be a compound 100 having ageneral structure

When, for example, Z is 2 a compound 100c may be a compound 100a havinga general structure

When, for example, Z is 3 a compound 100c may be a compound 100d havinga general structure

In some embodiments, a compound may include a bridged polycycliccompound formed from two corner units (e.g., compound 100b). Compound100b may be formed by coupling a multifunctional (e.g., trifunctional)corner unit A with a second multifunctional (e.g., trifunctional) cornerunit A as depicted in Scheme 2a.

In some embodiments, a compound 102 may have a general structure

Compound 102 may include a moiety coupling corner unit A with linkerunit L, the moiety including a nitrogen.

In some embodiments, a compound 103 may have a general structure

In some embodiments, R¹ may be independently alkyl, substituted alkyl,aryl, substituted aryl, N, N⁺R³, heterocycle, or substitutedheterocycle. R² may be independently alkyl, substituted alkyl, aryl,substituted aryl, heterocycle, substituted heterocycle, covalent bond,or alkene. R³ may be independently a pharmaceutically active agent,alkyl, substituted alkyl, aryl, substituted aryl, heterocycle,substituted heterocycle, alkene, ether, PEG, contains boron, or PEI. R⁴may be independently alkyl, substituted alkyl, aryl, substituted aryl,N⁺R³, heterocycle, substituted heterocycle, alkyl ether, PEG, PEI,ether, or alkene. R⁴ may independently include amide, alcohol, ester,sulfonamide, or sulfanilamide. R⁴ may be independently alkyl,substituted alkyl, aryl, substituted aryl, heterocycle, substitutedheterocycle, ether, amide, alcohol, ester, sulfonamide, sulfanilamide,or alkene. Z may include at least one bridge.

In some embodiments, at least one of the bridges may be —R²—N⁺R³₂—R⁴—N⁺R³ ₂—R²—. Each bridge may independently couple R¹ to R¹. In someembodiments, at least one of the bridges may be —R²—NR³—R⁴—N⁺R³ ₂—R²—.Each bridge may independently couple R¹ to R¹. In some embodiments, atleast one of the bridges may be —R²—NR³—R⁴—NR³—R²—. Each bridge mayindependently couple R¹ to R¹. In some embodiments, at least one of thebridges may be —R²—N═R⁴═N—R²—. Each bridge may independently couple R¹to R¹.

For example when Z is 1 compound 103a may be a compound 104b having ageneral structure

When, for example, Z is 2 a compound 103a may be a compound 104c havinga general structure

In some embodiments, a pharmaceutically active agent may includeguanidine or a derivative of guanidine. Chlorhexidine is a chemicalantiseptic. Chlorhexidine functions as a bactericidal to bothgram-positive and gram-negative microbes. It is considered lesseffective with some gram-negative microbes. Chlorhexidine is consideredbacteriostatic. The mechanism of action is believed to be membranedisruption, in a similar manner to the quaternary ammonium saltsdiscussed herein. A known guanidine is Chlorhexidine having a structure

In some embodiments, a guanidine derivative may include a moiety havinga structure (including a salt of the moiety)

In some embodiments, a guanidine derivative may include a moiety havinga structure (including a salt of the structures)

In some embodiments, a guanidine derivative may include an amidinemoiety.

In some embodiments, a pharmaceutically active agent may include ananti-viral agent.

In some embodiments, a pharmaceutically active agent may include atopical agent.

In some embodiments, a pharmaceutically active agent may include anantigen blocking agent.

In some embodiments, a pharmaceutically active agent may include anallergen blocking agent.

In some embodiments, a pharmaceutically active agent may include anantifungal agent.

In some embodiments, a pharmaceutically active agent may includeantimicrobial agents.

In some embodiments, an example of a compound 104b may include compoundshaving a general structure:

Z may include

In some embodiments, Z may include at least two bridges.In some embodiments, a chemical composition may include a chemicalcompound, wherein the chemical compound has a general structure:

including combinations of Z, X and/or NaOAc as R³ or

Z may include

including combinations of Z, X and/or NaOAc,

R₃ may include any substituent as described herein in relation tosimilar bridged polycyclic compounds. R₃ may include aryl, substitutedaryl, alkyl, substituted alkyl, and/or hetero atom containing groups. Insome embodiments, R₃ may include

Y may include, for example a halogen (e.g., Cl). Y may include aryl,substituted aryl, alkyl, and/or substituted alkyl. In some embodiments,R₃ may include

In some embodiments, R₃ may include a guanidine moiety and/or asubstituted guanidine moiety. In some embodiments, R₃ may include ahalogenated aryl group

n may range from 1-10, 2-8, 2-4, 3-6, 2-3, or 1-3. In some embodiment, nmay be 2. In some embodiments, a z may represent a charge on thechemical compound and an appropriate number of counterions. z may rangefrom 1-16, 2-14, 6-14, or 8-14. In some embodiments, y may represent anumber of bridges coupling the Nitrogens of the chemical compound. y mayrange from 3-8, 3-5, or 3-4.

In some embodiments, compounds such as 104b (e.g., 10-24) may includesalts of the compounds. Salts may include organic and/or inorganiccounterions. Counterions may include a singly or a multiply charged ion.Counterions may include a singly or a monomer or a polymer ion.Counterions may include an acetate ion, a carbohydrate ion, a saccharideion, or a sugar ion.

Counterions may include any of the examples described herein. In someembodiments, a salt of 104b (e.g., 10-24) may include an acetatecounterion. A salt of 104b (e.g., 10-24) may include a charge from 1-20,1-14, 4-14, 6-14, 4-10, or 4-8.

In some embodiments, a compound 103 may have a general structure

In some embodiments, R¹ may be independently alkyl, substituted alkyl,aryl, substituted aryl, N, N⁺R³, heterocycle, or substitutedheterocycle. R² may be independently alkyl, substituted alkyl, aryl,substituted aryl, heterocycle, substituted heterocycle, covalent bond,or alkene. R³ may be independently a pharmaceutically active agent,alkyl, substituted alkyl, aryl, substituted aryl, heterocycle,substituted heterocycle, alkene, ether, PEG, or PEI. R⁴ may beindependently alkyl, substituted alkyl, aryl, substituted aryl, N⁺R³,heterocycle, substituted heterocycle, alkyl ether, PEG, PEI, ether,contains boron, or alkene. R⁴ may independently include amide, alcohol,ester, sulfonamide, or sulfanilamide. R⁴ may be independently alkyl,substituted alkyl, aryl, substituted aryl, heterocycle, substitutedheterocycle, ether, amide, alcohol, ester, sulfonamide, sulfanilamide,or alkene. X may be one or more counter ions. Z may include at least onebridge.

In some embodiments, at least one of the bridges may be —R²—N⁺R³₂—R⁴—N⁺R³ ₂—R²—. Each bridge may independently couple R¹ to R¹. In someembodiments, at least one of the bridges may be —R²—NR³—R⁴—N⁺R³ ₂—R²—.Each bridge may independently couple R¹ to R¹. In some embodiments, atleast one of the bridges may be —R²—NR³—R⁴—NR³—R²—. Each bridge mayindependently couple R¹ to R¹. In some embodiments, at least one of thebridges may be —R²—N═R⁴═N—R²—. Each bridge may independently couple R¹to R¹.

For example when Z is 1 compound 103 may be a compound 104 having ageneral structure

When, for example, Z is 2 a compound 103 may be a compound 104a having ageneral structure

In some embodiments, a compound 104 may have a general structure

In some embodiments, R¹ may be alkyl, substituted alkyl, aryl,substituted aryl, N⁺R³, heterocycle, or substituted heterocycle. R² maybe alkyl, substituted alkyl, aryl, substituted aryl, N⁺R³, heterocycle,substituted heterocycle, covalent bond, or alkene. R³ may be alkyl,substituted alkyl, aryl, substituted aryl, heterocycle, substitutedheterocycle, alkyl ether, PEG, PEI, or alkene. R⁴ may be alkyl,substituted alkyl, aryl, substituted aryl, N⁺R³, heterocycle,substituted heterocycle, alkyl ether, PEG, PEI, ether, or alkene. R⁴ mayinclude amide, alcohol, ester, sulfonamide, or sulfanilamide. X may beone or more counter ions.

In some embodiments, counterions may include one or more halogens (e.g.,Br, Cl, I, etc.). A specific embodiment of a halogen counterion mayinclude Iodine which has proven as a more effective counterion forantimicrobial compounds. As has been discussed herein, counterions mayaffect the properties of the chemical compound and subsequentcomposition. Boron based counterions may increase certain antimicrobialproperties (e.g., BF₄ ⁻).

In some embodiments, salts of specific counterions may be added to apharmaceutical composition to increase the effectiveness of thecomposition. For example, any of the counterions described herein foruse in making the bridged polycyclic compound (e.g., counterions whichincrease a pharmaceutically active agent's effectiveness of thecompound), may be added to the composition later (e.g., as a salt suchas sodium or potassium tetrafluoroborate). In some embodiments, acombination of the two strategies may be used, additionally allowing fortwo or more different counterions or salts to be included in the finalformulation of the composition. Each of the counterions and/or salts mayincrease the effectiveness of the composition in a different manner.Other examples of counterions (which may be added as an appropriate saltlater in an ion exchange or a desired salt may be used during synthesisof the bridged polycyclic compound) may include an anion, a polymer, amonomer, a halogen, an iodine, a bromine, a chlorine, a triflate, atosylate, a boron, a borate, tetrafluoroborate, a nitrogen containinggroup, a nitrate, a halogen, a hexafluorophosphate, an acetate, or anNTf₂ (wherein Tf is bis(trifluoromethanesulfonyl)imide).

In some embodiments, a compound may include one or more guest moleculescoupled to the compound such as compound 106 having a general structure

In some embodiments, R¹ may be alkyl, substituted alkyl, aryl,substituted aryl, N, N⁺R³, heterocycle, or substituted heterocycle. R²may be alkyl, substituted alkyl, aryl, substituted aryl, N⁺R³,heterocycle, substituted heterocycle, covalent bond, or alkene. R³ maybe alkyl, substituted alkyl, aryl, substituted aryl, heterocycle,substituted heterocycle, alkyl ether, PEG, PEI, or alkene. R⁴ may bealkyl, substituted alkyl, aryl, substituted aryl, N⁺R³, heterocycle,substituted heterocycle, alkyl ether, PEG, PEI, ether, or alkene. M mayinclude one or more guest molecules associated with one or more portionsof compound 107 (e.g., amines). M may be one or more metals. M mayinclude silver, zinc, copper, gold, calcium, nickel, cobalt, barium,strontium, lead, lanthanum, iron, manganese, cadmium, magnesium,yttrium, lanthanum, cesium, praseodymium, neodymium, europium,gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, oralkaline earth metals or cesium. In some embodiments, M may includeorganic cation salts as templates (e.g., trimethyl ammonium, etc.). Mmay include light activated elements such that an antiviral oranticancer property of M is increased. X may be one or more counterions.

In some embodiments, M may be one or more guest molecules. X may be oneor more counter ions. M (e.g., Ag+ counter ion) may bind thereby keepingM in close proximity (e.g., F-ions have been reported and verified byx-ray single crystal structure to bind in ammonium salt cavitands). Ananion may bind to an ammonium thus affording a close association of thecation counterion. In some embodiments, M may pi-bond coordinate to R₄(e.g., aryl) or a heterocycle binding (e.g., pyridiyl nitrogen to a Ag+or a phenol —OH or O— binding to the Ag+).

In some embodiments, a compound may include one or more guest moleculescoupled to the compound such as compound 108 having a general structure

In some embodiments, R¹ may be alkyl, substituted alkyl, aryl,substituted aryl, N⁺R³, heterocycle, or substituted heterocycle. R² maybe alkyl, substituted alkyl, aryl, substituted aryl, N⁺R³, heterocycle,substituted heterocycle, covalent bond, or alkene. R³ may be alkyl,substituted alkyl, aryl, substituted aryl, heterocycle, substitutedheterocycle, alkyl ether, PEG, PEI, or alkene. R⁴ may be alkyl,substituted alkyl, aryl, substituted aryl, N⁺R³, heterocycle,substituted heterocycle, alkyl ether, PEG, PEI, ether, or alkene. M maybe one or more metals. M may include silver, zinc, copper, gold,calcium, nickel, cobalt, barium, strontium, lead, lanthanum, iron,manganese, cadmium, magnesium, yttrium, lanthanum, cesium, praseodymium,neodymium, europium, gadolinium, terbium, dysprosium, holmium, erbium,thulium, ytterbium, or alkaline earth metals or cesium. In someembodiments, M may include organic cation salts as templates (e.g.,trimethyl ammonium, etc.). M may include light activated elements suchthat an antiviral and/or anticancer property of M is increased. X may beone or more counter ions.

It should be understood that any of the compounds depicted herein may ormay not have one or more metals coupled to the structure. For example, astructure depicted with a metal associated with the compound alsoincludes a compound without a metal associated with the compound. Astructure depicted without a metal associated with the compound alsoincludes a compound with a metal associated with the compound. Althoughin many instances metals depicted herein are shown positioned within aspace defined by compounds described herein, this should not be seen aslimiting, metals may be coupled (e.g., complexed to) to a compound alongan outer surface of the compound.

Metals may include any elements in the periodic chart designated asmetals, known to one skilled in the art. In some embodiments, metals mayinclude any cationic metal known to one skilled in the art (e.g., Zn,Cu, Au, Ag, Cs, Mn, Mg, Ca, Ni, Co, etc.). In some embodiments, metalsmay include metals which have antiviral and/or anticancer propertiesand/or anti-inflammatory properties (e.g., Ag, Zn, etc.). In someembodiments, metals may function to couple one or more atoms ormolecules within a compound (e.g., compound 108) and/or to the surfaceof the compound. In some embodiments, one or more metals coupled to acompound may include one or more inorganic/organometallic compounds. Acompound (e.g., a bridged polycyclic compound) may include two or moredifferent metals coupled (e.g., associated in some way) to the compound.In some embodiments, a metal may be coupled to a bridged polycyclicmolecule.

In some embodiments, R¹ may be N⁺(1-22C alkyl), N⁺(1-12C alkyl), N⁺(1-6Calkyl), N⁺(6C alkyl), N⁺R³,

cyclam, aza crown ether, tris ethylamine N substituted cyclam, or

In some embodiments, R² may be 1-2C alkyl, 1-6C alkyl, 2-4C alkyl, CH₂,or a bond (e.g., covalent, ionic) between R¹ and a N of, for example,compound 108.

In some embodiments, R³ may be hydrophobic or hydrophilic. R³ may be1-3C alkyl, 4-5C alkyl, 6-10C alkyl, 7-9C alkyl, 10-22C alkyl, 15-22Calkyl, 6-10C alkyl ether, 7-9C alkyl ether, methyl, PEI(polyethyleneimine), or PEG (polyethyleneglycol). R³ may be 6C alkyl. R³may be a polymer. R³ may be an oxazoline polymer.

In some embodiments, R⁴ may include alkyl or substituted alkyl.

In some embodiments, R⁴ may be an aryl, substituted aryl, heterocycle,or substituted heterocycle. R⁴ may be

Forming one or more portions of a compound from one or more aromaticrings may provide advantages. Advantages may include providing rigidityto the compound enhancing the stability of the compound. Aromatic ringsmay facilitate the self-assembly of the constituent parts of thecompound. Other advantages may include pie stacking of compoundsrelative to one another or of “guests” positioned within the compound. Asubstituted aryl or heterocycle may include moieties (e.g., N) whichbind to other elements (e.g., metals such as silver) or molecules. R⁴may include substituents (e.g., R³) which effect properties of acompound as a whole (e.g., hydrophobicity, hydrophilicity,self-cleaning, antimicrobial, cross-coupling properties).

In some embodiments, a compound 108 may include an embodiment such ascompound 110 having a general structure

In some embodiments, R³ may be alkyl, substituted alkyl, aryl,substituted aryl, heterocycle, substituted heterocycle, alkyl ether,PEG, PEI, or alkene. R⁴ may be alkyl, substituted alkyl, aryl,substituted aryl, N⁺R³, heterocycle, substituted heterocycle, alkylether, PEG, PEI, ether, or alkene. M may include one or more “guest”molecules (e.g., one or more metals). X may be one or more counter ions.

In some embodiments, a compound 104 may include an embodiment such ascompound III having a general structure

In some embodiments, a compound 104 may include any number ofcombination of embodiments such as compound 113 having a generalstructure

-   -   Where:    -   113a is R^(3.1)═C₆H₁₃, R^(3.2)═CH₃ and R^(3.3)═R^(3.1) or        R^(3.2)    -   113b is R^(3.1)═C₈H₁₇, R^(3.2)═CH₃ and R^(3.3)═R^(3.1) or        R^(3.2)    -   113c is R^(3.1)═C₁₀H₂₁, R^(3.2)═CH₃ and R^(3.3)═R^(3.1) or        R^(3.2)    -   113d is R^(3.1)═C₁₂H₂₅, R^(3.2)═CH₃ and R^(3.3)═R^(3.1) or        R^(3.2)    -   113e is R^(3.1)═C₆H₁₃, R^(3.2)═CH₂Ph and R^(3.3)═R^(3.1) or        R^(3.2)    -   113f is R^(3.1)═C₁₂H₂₅, R^(3.2)═CH₂Ph and R^(3.3)═R^(3.1) or        R^(3.2)    -   113his R^(3.1)═C₄H₉, R^(3.2)═CH₃ and R^(3.3)═R^(3.1) or R^(3.2)

In some embodiments, a compound 104 may include a an embodiment such ascompound 114 having a general structure

In some embodiments, R³ may be alkyl, substituted alkyl, aryl,substituted aryl, heterocycle, substituted heterocycle, alkyl ether,PEG, PEI, or alkene. R⁴ may be alkyl, substituted alkyl, aryl,substituted aryl, N⁺R³, heterocycle, substituted heterocycle, alkylether, PEG, PEI, ether, or alkene. M may be one or more metals. X may beone or more counter ions.

Substituents (e.g., R³) may be configured to perform a variety offunctions. By using different substituents, properties of a compoundsuch as the bridged polycyclic compounds described herein may becustomized to meet a particular industrial and/or individual's need. Forexample, R³ may be hydrophobic or hydrophilic depending upon thespecific property needed.

In some embodiments, a substituent (e.g., R³) may be multifunctionalsuch that it imparts two or more properties to a formed compound. Forexample a substituent (e.g., R³) may function to increase thehydrophilicity of a compound, as well as, function as a cross-couplingreagent to cross-link compounds to one another under appropriateconditions (e.g., a substituent may include one or more heteroatomswithin its structure such as N, O, and S).

In some embodiments, substituents such as R³ may function to enhancehydrophobicity and/or lipophilicity. Depending upon the needs of acustomer the hydrophobicity/lipophilicity of a compound may beincreased. Adjusting the hydrophobicity/lipophilicity of a compound mayconsequently adjust the solubility of the compound in a particularsolvent and/or matrix. Increasing the liphophilicity of a substituent(e.g., R³) coupled to an ammonium salt may increase the anti-microbialactivity of a compound. In some embodiments, a compound may have aminimum inhibitory concentration (MIC) of less than 900 μM, of less than600 μM, or of less than 300 μM. A discussion of relationship betweensubstituent chain length and antimicrobial activity of quaternaryammonium salts may be found in Pernak et al., “Synthesis andanti-microbial activities of some pyridinium salts with alkoxymethylhydrophobic group” Eur. J. Med. Chem. 36 (2001) 899-907, which isincorporated by reference as if fully set forth herein.

The relationship between substituent chain length and antimicrobialactivity is demonstrated in tests conducted on 113a, 113b, 113d, 113e,and 113h detailed herein in the Examples portion. A series of bridgedpolycyclic compounds were synthesized wherein different substituentswere coupled to the quaternary ammonium moieties. Substituents includedC1, C4, C6, C8, C12, and benzyl in combinations of C1 with C4, C6, C8,and C12, as well as, combinations of benzyl with C6 and C12. Time killand residual surface tests of the antimicrobial strength of thecompounds were tested against examples of gram+bacteria (e.g.,Staphylococcus aureus, most common surgical wound infection),gram−bacteria (e.g., Escherichia coli, most commonly acquired hospitalinfection), and fungus (e.g., Aspergillus niger, a toxic black moldfound in residences). Of the various alkyl chains combined with C1tested, the C6,C1 compound tested as the strongest antimicrobialcompound. When the test results of the C6,C1 were compared to the benzylderivatives, once again, the C6,C1 derivative tested as the overallstrongest antimicrobial.

The 113a C6C1 compound is unique in regards to the relatively shortalkyl chain vs. known quaternary antimicrobials and high antimicrobialactivity. Discrete quaternary ammonium or pyridinium antimicrobialmolecules usually possess long alkyl chains. The most effective discrete(e.g., noncyclic) quaternary ammonium or pyridinium salt antimicrobialshave an alkyl chain length between 12 and 18 carbon atoms as describedby T. Loftsson et.al. in J. Med. Chem. 46, 2003, 4173-4181, which isincorporated by reference as if fully set forth herein.

In general it is known in the art that quaternary ammonium compounds areeffective biocidal agents when they possess an alkyl chain with at leasteight carbon atoms (S. Block, ‘Disinfection, Sterilization andPreservation’, 3^(rd) Ed., Lea and Febiger, Philadelphia, Pa., 1983;cited in ‘Recent Advances in Antimicrobial Dendrimers’, S. L. Cooperet.al. Adv. Mater. 2000, 12, no. 11, 843-846, which is incorporated byreference as if fully set forth herein). In a study of dendrimerquaternary ammonium salts, dendrimer biocides carrying C₁₀ alkyl chainswere the most potent (S. L. Cooper et.al. Biomacromolecules, 1 (3),473-480, 2000), which is incorporated by reference as if fully set forthherein.

Typically, non-discrete polymers are some of the only antimicrobials toshow any appreciable antimicrobial activity with alkyl groups of <8carbons. However, non-discrete polymers (e.g. polyethyleneiminequaternary ammonium containing polymers) demonstrated weaker overallantimicrobial activity in antimicrobial residual surface tests (A. M.Klibanov et.al. Biotechnology Letters, 25, 2003, 1661-1665), which isincorporated by reference as if fully set forth herein.

Furthermore, the straightforward route and synthesis efficiency makesbridged polycyclic compounds (e.g., 113a) more attractive from amanufacturing standpoint over the more laborious methods required fortypical dendrimer synthesis. Both bridged polycyclic compounds (e.g.,113a) and dendrimers have the advantage of being polyvalent (multiplepositively charged sites on one molecule to attract microbes) affordingincreased activity vs. traditional discrete quaternary ammonium salts(S. L. Cooper et. al. U.S. Pat. No. 6,440,405). However, the dendrimersynthesis requires large volumes of solvents/reagents relative toobtained product and long periods of time (days) to synthesize asdescribed by S. L. Cooper et. al. in U.S. Pat. No. 6,440,405, which isincorporated by reference as if fully set forth herein.

In some embodiments, substituents such as R³ may function to enhancehydrophilicity and/or lipophobicity. Depending upon the needs of acustomer the hydrophilicity/lipophobicity of a bridged polycycliccompound may be increased. Adjusting the hydrophilicity/lipophobicity ofa compound may consequently adjust the solubility of the compound in aparticular solvent and/or matrix.

In some embodiments, substituents such as R³ may function to enhance theself-cleaning properties of which the compound may impart to a surfaceto which the compound is coupled. In some embodiments, substituents mayenhance the antimicrobial properties of the compound. Self-cleaning andantimicrobial properties may function in combination with one another.

The search for self-cleaning surfaces has come about from theobservation of such natural surfaces occurring naturally in nature, suchas (e.g., lotus leaves). To clean a surface, material has to betransported along it, and best, off it. By tuning the wettability of thesubstrate, two basic options arise. The surface may be rendered verywettable, and the decontamination process is based on film flow. But,interestingly, biology hints at a different option. Non-wettable plantleaf surfaces, such as those of the famous Lotus plant, have a built-inelementary cleaning mechanism. This was noticed in the mid-nineties bybotanists studying plant surfaces. They observed that droplets runningoff the leaves may carry dry contaminants along. Self-cleaning surfacesare believed to be a combination of low surface-energy species and apeculiar topographic feature based on dual-size roughness: thecoarse-scale rough structure is about 10-20 μm, whereas the finerstructure on top of the coarse structure is in the range of 100 nm to 1μm. The dual-size structure has proven to be vital in generating thesuperhydrophobicity of the lotus leaves, especially for obtaining lowwater rolloff angles. Techniques for forming superhydrophobic surfacesmay be found in Ming et al., “Superhydrophobic Films from Raspberry-likeParticles” Nano Lett., 5 (11), 2298-2301, 2005, which is incorporated byreference as if fully set forth herein.

In some embodiments, a first compound described herein may include aplurality of second compounds coupled to the surface of the firstcompound. The first compound may be several times larger than the secondcompound. The first compound may be an order of magnitude or larger thanthe second compound. The first compound may include, but is not limitedto, compounds such as compound 100. Second compounds may be coupled toactive sites on the first compound to form a third compound. In someembodiments, the second compound may include, but is not limited to,compounds such as compound 100, coupled to active sites of a firstcompound. Coupling the third compound to a surface may provide thenecessary surface topography (e.g., a dual-roughness) to produce aself-cleaning surface.

In some embodiments, a topology of a surface treated with the coatingcompositions described herein may have at least one layer havingelevations whose average height may be from 20 nm to 25 μm and whoseaverage separation is from 20 nm to 25 μm, whose average height is from50 nm to 10 μm and/or whose average separation is from 50 nm to 10 μm,or whose average height is from 50 nm to 4 μm and/or whose averageseparation is from 50 nm to 4 μm. The topology of a surface treated withthe coating compositions described herein may have elevations whoseaverage height is from 0.25 to 1 μm and whose average separation is from0.25 to 1 μm. The average separation of the elevations is the separationbetween the highest elevation of an elevation and the most adjacenthighest elevation. If an elevation has the shape of a cone, the tip ofthe cone is the highest elevation of the elevation. If the elevation isa rectangular parallelepid, the uppermost surface of the rectangularparallelepid is the highest elevation of the elevation.

In some embodiments, a hydrophobic coating may be applied over aprotective coating including a self-cleaning topological surface.

In some embodiments, substituents (e.g., R³) coupled to portions of acompound may function as the finer structure relative to the coarserstructure of the compounds. Substituents such as R³ may increase thehydrophobicity of the compounds to which the substituents are coupled.

However, a disadvantage of the hydrophobic surfaces is that if thestructures are sufficiently complicated, (e.g., moldings with undercutsor porous moldings or sponges, water may not then penetrate these voids)the result being that the cleaning properties of the surface may beinhibited. The globular shape of the water droplets on these surfacesmay cause visual impairment if the droplets do not roll off from thesurface because the surface is, for example, horizontal. In suchinstances, highly wettable surfaces may be advantageous, since a waterdroplet on these becomes distributed over almost the entire surface andforms a film of minimum thickness. This occurs in particular if thesurface tension of the water is reduced by appropriate means (e.g.,surfactants) and/or a hydrophilic surface is present. In someembodiments, hydrophilic substituents (e.g., R³) may be coupled toactive sites (e.g., amines) on compounds described herein. In someembodiments, hydrophilic substituents/coatings (e.g., hydrophilicsilicas) may be coupled to compounds described herein. A discussion ofhydrophilic substances and particles may be found in U.S. PatentApplication, Publication No. 20050118911 to Oles et al. (“Oles”), whichis incorporated by reference as if fully set forth herein. Increasingthe hydrophilicity of a surface may inhibit microbial adhesion.Substituents for inhibiting microbial adhesion may be found in Ming etal., “Bacterial Adhesion at Synthetic Surfaces” APPLIED ANDENVIRONMENTAL MICROBIOLOGY, November 1999, p. 4995-5002, which isincorporated by reference as if fully set forth herein.

A self-cleaning surface including compounds may be enhanced bydecreasing the surface energy or increasing the hydrophobicity of theself-cleaning surface. Several different techniques may be used incombination with compounds to increase the hydrophobicity andself-cleaning properties of a surface.

In some embodiments, a surface may be first coated with a hydrophobicsubstance (e.g., a hydrophobic polymer) and followed by applyingcompounds to the coating. The hydrophobic substance may be a matrixwhich also reacts with active sites on provided compounds (e.g., siloxybased polymers). In some embodiments, compounds may be dispersed withina matrix before applying the matrix to a surface. The matrix may act asa low energy hydrophobic coating which also couples the compounds to thesurface after curing the matrix.

In some embodiments, counter ions for a bridged polycyclic compound maybe selected to adjust particular properties of a compound or tointroduce new properties to the compound. Adjusting properties of acompound based on a selection of a particular counter ion allows furthercustomization of a compound. In some embodiments, counter ions mayinclude counter ions which have or enhance antimicrobial propertiesand/or anti-inflammatory properties (e.g., boron, zinc). In someembodiment, counter ions may adjust the hydrophilicity or hydrophobicityof the complex. Counter ions may include metals. Research has held thatspecific counter ions do affect the antimicrobial activity of quaternaryammonium compounds.

Counter ions may include, but are not limited to, organic, inorganic, ororganometallic moieties. Examples of counter ions may include inorganicions (e.g., halogen ions, such as fluorine, bromine, chlorine andiodine), organic ions (e.g., tosylate, prosylate sulfuric acid, nitricacid and phosphoric acid, and ions of organic acids such as succinicacid, fumaric acid, lactic acid, glycolic acid, citric acid, tartaricacid and benzoic acid), or coordinate type anions (e.g., fluoro sulfateand tetrafluoro borate).

In some embodiments, counter ions may include a hydrophobic organicgroup (e.g., lauryl sulfate, dodecylbenzene sulphonate, diethylhexylsulphosuccinate, carboxylic acid derivatives with alkane, alkene oralkyne aliphatic tails such as myristic acid salts, octadecanate,dodecanoic acid salts, oleic acid salts, Palmitoleic acid salts, lauricacid salts, Stearic acid salts, phosphinic acid salts, phosphonic acidsalts (i.e. tetradecylphosphonate, hexadecylphosphonate) anddodecylsulphonate, dodecylsulfate anions).

In some embodiments, bridged polycyclic compounds may be polymerized.Polymers incorporating bridged polycyclic compounds may have molecularweights high enough to inhibit systemic absorption when, for example,ingested. The minimum molecular weight, and hence the degree ofpolymerization of bridged polycyclic compounds, required to inhibitsystemic absorption may be relatively low. Nonsystemic polymers mayinclude a minimum degree of polymerization of 3 or greater, 6 orgreater, 10 or greater, 20 or greater, or 50 or greater. In someembodiments, an enteric coating may be applied to a composition in orderto inhibit absorption and/or premature absorption.

In some embodiments, bridged polycyclic compounds may be polymerized inany number of ways known to one skilled in the art. Bridged polycycliccompounds may be polymerized using methods known to polymerize amines.In some embodiments, bridged polycyclic compounds (e.g., compounds 113herein) may be polymerized via the tertiary amines or the secondaryamines. For example, bridged polycyclic compound 401 may be polymerizedvia the tertiary amines.

In some embodiments, C1 may be polyethylene glycol (PEG), alkyl, and/oraryl. In some embodiments, X may include niacin, butyrate, a statin(e.g., Atorvastatin, Exetimibe), or other anionic counterion. Anybridged polycyclic compound described herein may be polymerized.

In some embodiments, a polymerized bridged polycyclic compound may besubstituted with linkers as described herein such that, for example,more pharmaceutical agents may be coupled to the polymer. For example,guanidine moieties may be used to replace the (H) of (—NH—), then add HXto form the salt of guanidine moiety and the cage amines to give higheroverall charge.

Synthesis of Bridged Polycyclic Compounds

For commercialization purposes compounds such as bridged polycycliccompounds (and their metal and/or metal oxide coated counterparts)require an efficient and cost effective method of synthesis. In someembodiments, bridged polycyclic compounds may be formed through theself-assembly of two or more compounds to form much larger complexsystem in fewer steps and more efficiently than traditional stepwisesynthetic means.

At the most general level, the words “self-assembly” are used toidentify the phenomenon whereby some kind of higher-level patternemerges from the interactions of multiple simple components. An exampleof self-assembly from the Stang group is shown in Scheme 1 (Stang, P.J.; Cao, D. H. J. Am. Chem. Soc. 1994, 116, 4981). To set thisparticular type of self-assembly in its proper context, it should benoted that in the field of chemistry, the term “self-assembly” is usedto describe two distinct types of processes. On the one hand, there areassemblies that lead to the formation of essentially infinite arrays,while on the other hand, there are assemblies such as that shown inScheme 1 that lead to distinct, bounded species. Furthermore, withineach of these categories, it is possible to make a further distinctionthat reflects the scale of organization. For example, for infinitearrays, one may consider processes such as crystallization, where themolecules are ordered at the molecular level (ca. 10⁻⁹ m), or theformation of self-assembled monolayers and bilayers, where there islittle order between individual molecules, but a larger scale oforganization is evident across say the 10⁻⁶ m level. Likewise, the scaleof organization for assemblies leading to distinct species may be brokendown into similar categories. It may be noted the self-assembly ofmacroscale objects (10⁻³ m) is currently being investigated. However, asfar as the interaction of molecules to form distinct species goes, itmay be considered the formation of micelles and vesicles thatconstitutes assembly at the 10⁻⁶ m level.

The essential features of chemical assembly processes is that they sharea common self-correcting mechanism. In other words, strictself-assemblies are fully reversible, dynamic, systems that lead to aproduct that represents the global thermodynamic minimum for the system.Sometimes an additive or template is needed to boost the efficiency ofthe assembly, but this is the only true variable if one is speaking ofstrict self-assembly. At their cores, strict molecular assembliesconsist of subunits, product, and an equilibrium that relates the two.

In some embodiments, self-assembly techniques (e.g., dynamic covalentchemistry) may be employed to synthesize stable compounds, which arethemselves large enough to be described as nanoparticles and/or whichmay be used to form nanoparticles.

Bridged polycyclic compounds represented by compounds 104 and 108 may besynthesized by any means known to one skilled in the art. As has beenmentioned, self-assembly may be a useful technique for efficientlysynthesizing nanoparticles described herein. In some embodiments,nanoparticles such as compounds 104 and 108 may be formed viaself-assembly using Schiff base condensation reactions between aminesand aldehydes to form an imine as depicted in Scheme 3. For example, atrifunctional amine (e.g., tris(2-aminoethyl)amine (TREN)) may bereacted with a bifunctional aldehyde (e.g., ethane-1,2-dione (glyoxal)).

In Scheme 3, the amine depicted is trifunctional and the aldehyde isbifunctional. However, the example depicted in Scheme 3 should not beseen as a limiting embodiment. For example, a Schiff base condensationreaction is depicted in Scheme 4 in which the amine is bifunctional andthe aldehyde is trifunctional.

In some embodiments, two different trifunctional molecules may bereacted with one another in order to form an asymmetric adduct. Scheme4a depicts an embodiment of the formation of an asymmetric adduct.

For example, a trifunctional amine (e.g., tris(2-aminoethyl)amine(TREN)) may be reacted with a trifunctional aldehyde (e.g.,1,3,5-aldehyde substituted phenyl). Triethanolamine may befunctionalized at the OH with an aminoacid to giveN—(CH₂CH₂OC(O)Phenyl(CHO). N—(CH₂CH₂OC(O)Phenyl(CHO) may be reacted withany triamine to give an asymmetric example of a bridged polycycliccompound. A discussion of synthesis techniques for differentmultifunctional ligands (e.g., trifunctional aldehydes) may be found inChand et al. “Synthesis of a Heteroditopic Cryptand Capable of Imposinga Distorted Coordination Geometry onto Cu(II): Crystal Structures of theCryptand (L), [Cu(L)(CN)](picrate), and [Cu(L)(NCS)]{picrate) andSpectroscopic Studies of the Cu(II) Complexes” Inorg Chem 1996, 35,3380-3387, which is incorporated by reference as if fully set forthherein.

In some embodiments, formation of a bridged polycyclic compound (e.g.,Schemes 4, 4a, or 5) may be carried out in an alcohol (e.g., ethanol).

A more specific example of the self-assembly Schiff base condensationstrategy depicted in Scheme 3 is depicted in Scheme 5 showing theformation of imine compound 116. Imine compound 116 may be used as anintermediate toward the formation of compound 110.

A Schiff base condensation may be carried out using an acid catalyst(e.g., acetic acid). A Schiff base condensation may be carried out usingany means known to one skilled in the art. Techniques for amine aldehydecondensations may be found in U.S. Patent Application, Publication No.2004/0267009 to Redko et al. (“Redko”), which is incorporated byreference as if fully set forth herein.

In some embodiments, a reduction may be carried out in an alcohol (e.g.,ethanol and/or methanol) with a reducing agent (e.g., sodiumborohydride).

In some embodiments, coupling of corner units or corner units and linkerunits to form bridged polycyclic imine compounds may be carried out inan alcohol (e.g., ethanol and/or methanol) based solvent. In someembodiments, reduction of at least some of the imines may be carried outwithout any substantial work up directly following the coupling step(e.g., by adding a reducing agent such as sodium borohydride) to form abridged polycyclic compound.

In the past reactions such as the coupling and reduction steps have beencarried out as two totally separate steps involving for example workingup (e.g., purifying and isolating) the reaction after the coupling stepbefore the reducing step. One or more of these steps (e.g., the couplingstep) have in the past been carried out in for example acetonitrileresulting in a seemingly polymeric substance, followed by an isoxolateextraction. In reality the isoxolate extraction may have been merelydriving the reaction towards the bridged polyclic product, by conversionof polymer and oligomer products.

Running the reactions in a solution of heated ethanol results in almostquantitative yields of the desired product without any substantial workup or isolation protocols.

In some embodiments, coupling of corner units or corner units and linkerunits to form bridged polycyclic imine compounds may be carried out in agreen solvent. In some embodiments, a green solvent may include anysolvent which is naturally occurring and which has been found not toharm the environment when used on an industrial scale. In someembodiments, a green solvent may include water or an alcohol basedsolvent (e.g., ethanol). A catalyst may be used to run the reaction inwater. In some embodiments a catalyst may include aniline. A similarmethod is described in Angewante Chemie Vol. 45, pages 75-81, which isincorporated by reference as if fully set forth herein.

In another example of functionalizing an amine at least in part defininga bridged polycyclic compound, a functionalized substituent may becoupled to the amine. A functionalized substituent may include an alkylamine group. A non-limiting example of an alkyl amine may include—CH₂CH₂CH₂NH(CH₂)₅CH₃. The amine may be further functionalized. Forexample the amine of the alkyl amine may be alklyated such that anotherquaternary amine is available increasing the antimicrobial activity ofthe bridged polycyclic compound. The synthesis of such an embodiment isdetailed in the Examples section.

In some embodiments, following a reduction to form a bridged polycyclicamine, such as compound 120 or a compound such as compound 301 having astructure

a linking agent (e.g., to couple a pharmaceutically active agent to) ora pharmaceutically active agent may be coupled to a bridged polycyclicamine such as compound (301). Linking agents may be, for example, any ofthe compounds or reagents identified herein as R³.

Following are some representative example of activating agents and howto synthetically couple them to compounds such as compound 301.

Following is a representative example of how to synthesize a bridgedpolycyclic compound including a pharmaceutically active agent coupled tothe bridged polycyclic compound.

In some embodiments, it may be advantageous to increase the number ofactive sites on to which to couple pharmaceutically active agents suchas depicted directly below in the following two schemes.

Following are some representative examples of pharmaceutically reactiveagents and how to synthetically couple them to linking agents and/orbridged polycyclic compounds such as compound 301.

Compositions Comprising Bridged Polycyclic Compounds

In some embodiments, bridged polycyclic compounds may be incorporatedinto a composition which is substantially nontoxic to an animal and/orhuman. A composition may include a solvent capable of dissolving abridged polycyclic compound. In some embodiments, a composition mayinclude an environmentally green solvent. A solvent may include waterand/or ethyl alcohol. In some embodiments, a composition may consist ofwater and a bridged polycyclic compound. Such compositions may beadministered using any method described herein including, but notlimited to, orally, topically, intravenously, absorbed through the skin,injected, etc.

In some embodiments, a topical composition may include a flavoring. Aflavoring may include something an animal may find palatable. Forexample a flavoring may include malt extract, xylitol, splenda,sucralose or any sweetener. A flavoring may range from 0.01% to 0.10%,0.10% to 1.0%, or 1.0% to 10.0% of a composition. In some embodiments, aflavoring may include something an animal finds unpalatable. Anunpalatable flavoring may discourage an animal from licking their feetand exacerbating their condition and/or accidentally removing theapplied composition.

In some embodiments, a composition may include a colorant. A colorantmay include D&C Blue #1 or any FDA approved color. A colorant may rangefrom 0.001% to 0.010%, 0.010% to 0.10%, or 0.10% to 1.0% of acomposition.

In some embodiments, a composition may include a fragrance.

In some embodiments, a composition may include additional additiveswhich may function in combination or separately from the bridgedpolycyclic compound in solution. Additives may function to improve asubject's health. Additives may include vitamins including, but notlimited to, vitamins D and E.

In some embodiments, different compositions may be formulated fordifferent types of users. For professionals users (e.g., doctors,veterinaries), compositions may include a greater percentage of activebridged polycyclic compounds than compositions formulated for over thecounter sale to nonprofessionals. Professional compositions may notinclude flavorings or colorants.

While previous discussions herein have concentrated on the use ofbridged polycyclic compounds for treating maladies animals such ascommon household pets including canines and felines, theses examplesshould not be seen as limiting. Compositions described herein may beused to treat other animals (e.g., mammals) including, but not limitedto, avian (e.g., birds), reptiles, horses, swine, ferret, guinea pig,sheep, goats, deer, tigers, and/or lions. Especially of interest wouldbe to treat animals which are raised in a controlled environment (e.g.,for consumption, for consumption of animal byproducts). Domesticatedanimals raised in a controlled environment are typically raised in verycrowded and even overcrowded conditions. Overcrowded conditions areconducive to greater incidences of foot maladies. Animals raised forconsumption benefiting from the herein described composition mayinclude, but are not limited to, cattle (e.g., beef, dairy), goats,sheep, rabbits, swine, deer, guinea pigs, turkey, ostriches, andchickens.

In some embodiments, compositions including bridged polycylic compoundsmay be administered to treat otic maladies. Otic maladies may include,but are not limited to, ear mites or ear infections. Otic maladies mayinclude otitis externa. Otitis externa is generally characterized as aninflammation of the outer ear and ear canal. Otic maladies may includeotitis media. Otitis media is generally characterized as an inflammationof the middle ear. Otic maladies may result from bacteria associatedwith otic maladies. Bacteria treatable with compositions describedherein may include, but are not limited to, Staphylococcus, Pseudomonasaeruginosa, Enterobacter, Proteus mirabilis, Aeromonas hydrophila,Streptococcus and Klebsiella pneumoniae. Otic maladies may result fromfungus associated with otic maladies. Fungus treatable with compositionsdescribed herein may include, but are not limited to, Malasseziapachydermatis, Candida albicans, and Aspergillus.

In some embodiments, compositions including bridged polycylic compoundsmay be used to treat otic maladies in the form of an ear cleanser, earwash, and/or ear drops. In some embodiments, a composition (e.g., oticcomposition) may include glycerin, propylene glycol, polyethylene,mineral oil, benzyl alcohol, and/or ethyl alcohol. A composition mayinclude a fluid with a high boiling point (e.g., an oil, mineral oil)which may function to spread active ingredients over a surface.

In some embodiments, compositions described herein may be appliedtopically before, during, and/or after a surgical procedure (e.g., at oraround a surgical site or a suture site to inhibit secondaryinfections).

Additional otic compositions which may be used to deliver bridgedpolycyclic compounds, as well as additional uses, are described in U.S.Pat. No. 5,753,268 to Stolle et al., U.S. Pat. No. 5,753,269 to Groh etal., and U.S. Pat. No. 5,597,560 to Bergamini et al., which areincorporated by reference as if fully set forth herein.

In some embodiments, compositions including bridged polycyclic compoundsmay be administered topically. For example, compositions may beadministered topically to treat bacterial infection, fungal infection,viral infection, and for general wound healing (e.g., cuts, sores,scrapes). Compositions may be administered topically in the form of, forexample, a topical spray, body wash (e.g., for treating animals tocontrol fungal, bacterial, and other microbial infections, includingitching, flaking, hot spots, rashes, dryness, etc.), and/or a shampoo(e.g., for treating scalp related problems). Compositions may beadministered topically as a disinfectant and healing agent for burns,small cuts, abrasions, and/or bites. Compositions may be administeredtopically to inhibit and/or ameliorate a variety of skin conditionsincluding, but not limited to, bed sores, eczema, bacterial infections,rashes, insect bites (including but not limited to the inflammation andpain associated with insect bites), poison ivy, minor scrapes, boils,and/or sores. Compositions may be applied topically as lotions (e.g., tocontrol germs, skin moisture, condition and promote healing). Topicalapplications may be used to treat parasites. Parasites may include, forexample, fleas, ticks, and/or lice. Parasites may include, for example,heart worms and/or ring worms. Compositions may be administeredtopically to inhibit and/or ameliorate acute-chronic fungal infectionssuch as ringworm, athlete's foot, jock itch, etc., as well as, otherfungal infections (e.g., fingernail and toenail fungus). Compositionsmay be administered topically to inhibit and/or ameliorate Idiopathicdermatology problems-generalized pruritis (itching). Compositions may beadministered topically to inhibit and/or ameliorate Atopic and contactdermatitis (assists in soothing, reducing inflammation, and stimulateshealing). Common examples: itchy skin following contact with lawn grass,or other irritant, which can provoke the need to scratch the points ofcontact.

In some embodiments, compositions including bridged polycyclic compoundsmay be administered topically for uses commonly associated with themedical field (animal and human). For example topical application of thecompositions described herein may be used to inhibit and/or amelioratetopical staph infection. Compositions may be applied topically as handsoap (e.g., for controlling germs beyond currently availableantibacterial soaps). Compositions may be used as a medical laboratorypersonnel antimicrobial hand wash for cross infection and contaminationinhibitor (e.g., as an instant hand sanitizer).

In some embodiment, topical compositions described herein may functionto inhibit and/or ameliorate any topical skin infections, diseases,bacteria, and/or fungus. Topical compositions described herein mayfunction to inhibit and/or ameliorate any symptoms and/or secondaryinfections related to topical skin infections, diseases, bacteria,and/or fungus. In some embodiments, topical compositions describedherein may function to inhibit and/or ameliorate pododermatitis.Pododermatitis is a term that includes any malady which results in theinflammation of at least a portion of the feet. In some embodiments,topical compositions described herein may function to inhibit and/orameliorate interdigital furunculosis. Interdigital furunculosis(sometimes referred to as interdigital cysts) are painful nodularlesions located in the interdigital webs of dogs. In some embodiments,topical compositions described herein may function to inhibit and/orameliorate pyoderma, bacterial dermatitis, and/or yeast infections.

Demanding requirements such as those for topical materials also exist innumerous other products such as coatings. Recent developments innanotechnology are increasingly being considered to address theserequirements. A key challenge to widespread adoption of nanotechnologyto such applications is the ability to manufacture non-agglomerateddiscrete nanoparticles that can be homogeneously distributed in resinsor coatings to produce nanocomposites.

In some embodiments, a topical composition may include bridgedpolycyclic compounds. At least one of the bridged polycyclic compoundsmay include at least two cyclic groups. At least two of the cyclicgroups may include quaternary ammonium or amine moieties. In someembodiments at least two of the cyclic groups may be defined at least inpart by quaternary ammonium moieties. Bridged polycyclic compounds mayinclude any of the compounds described herein.

In some embodiments, a composition may be applied to a topical surfaceor at least to a portion of a topical surface.

In some embodiments, a topical composition may include core-shellnanoparticles as described herein.

In some embodiments, a topical composition may include nanoparticles asdescribed herein.

A topical composition and method of use of the same may be used inrestoring the function and anatomy of at least a portion of an animal'sfoot. Topical compositions as described herein may be used in bondingagents, foams, sealants, varnishes, gels and resins. Topicalcompositions may include polymerizable unsaturated monomers, oligomers,prepolymers, or combinations thereof. Topical compositions may inhibittooth decay and/or microbial growth in and around at least a portion ofan animal's foot. Topical compositions may inhibit secondary infections.

Some commonly found bacteria leading to topical maladies have been knownfor some time (e.g. Staphylococcus aureus being the most common bacteriaisolated from instances of pododermatitis). Other bacteria which lead totopical maladies may include Streptococcus mutans.

FIGS. 1-3 depict a graphical representation of time kill assay tests forbridged polycyclic compound 5 tested against HaemophilusActinomycetemcomitans, Streptococcus mutans, and Porphymonas Gingivalisrespectively. The test results demonstrate how effective bridgedpolycyclic compounds are against known destructive microbes.

In some embodiments, topical compositions may enhance sustainedantimicrobial activity with minimum harm to the living structure andsurrounding tissues and without affecting the composition's restorativeproperties.

In some embodiments, topical compositions described herein may be usedfor topical trauma treatment. Topical composition may be used fortopical trauma treatment field kits used for the temporary or permanenttreatment of topical trauma out in the field when specialized help isnot readily available. Topical compositions may be used in combinationwith gelators, absorbents, and/or coagulating agents to prepareantimicrobial wound dressings.

Nanoparticles have been shown to enable nearly 50% reduction in fillingshrinkage. These nanocomposites are suggested to be particularly usefulfor fabricating load bearing and cosmetic restorations.

A topical composite may have a high strength required for load-bearingrestorations, yet maintains a glossy appearance, even after substantialwear. A load-bearing application associated with topical applicationsmay include rebuilding a damaged/excised portion of an animal's nailand/or hoof. Through the use of particles having a mean particle sizebetween about 0.05 .mu.m and about 0.50 micromolar, the composite isuseful in stress bearing restorations and in cosmetic restorations. Thestructural filler used is typically ground to a mean particle size ofless than 0.5 micromolar and also includes a nanofiller having discreteparticles of a mean particle size less than 100 nm to improve handlingand mechanical characteristics. The preferred topical compositesmaintain their surface finish even after substantial use and also havethe strength properties of hybrid composite resins.

In some embodiments, a topical composite, comprising: a polymerizableresin base; and about 10% by volume to about 80% by volume fillerconsisting essentially of a ground structural filler and a non-groundnanofiller, wherein the ground structural filler comprises between about10% by volume and about 70% by volume of the composite and consists ofground particles of mean particle size between about 0.05 μm and about0.50 μm, and wherein the ground structural filler contains less than 50%by volume of particles above 0.5 μm in diameter, and wherein thenon-ground nanofiller comprises between about 1.0% by volume and about15% by volume of the composite and consists essentially of discrete,non-aggregated gamma alumina particles having a mean particle size ofabout 40 nm or less.

The resin composite, in the cured form, may have a flexural strength ofat least 100 MPa.

The resin composite, in the cured form, may have a flexural strength ofat least 120 Mpa.

The resin base comprises a polymerizable vinyl compound.

The ground structural filler contains less than 10% by volume ofparticles above 0.8 micromolar in diameter.

The non-ground nanofiller comprises between about 5 and about 12% byvolume of the composite.

A topical composite comprising: a polymerizable resin base; and about11% by volume to about 80% by volume filler in the resin base, thefiller consisting essentially of a ground structural filler and anon-ground nanofiller, wherein the ground structural filler comprisesbetween about 10% by volume and about 70% by volume of the composite andconsists of ground particles having a mean particle size of betweenabout 0.05 .mu.m and about 0.50 .mu.m, and wherein the non-groundnanofiller comprises between about 1.0% by volume and about 15% byvolume of the composite and consists essentially of discrete,non-aggregated aluminosilicate particles having a mean particle size ofless than about 100 nm, and a 1:4 molar ratio of alumina to silica.

The resin composite, in the cured form, has a flexural strength of about120 MPa or greater.

The resin base includes a polymerizable vinyl compound.

The non-ground nanofiller comprises between about 5% by volume to about12% by volume of the composite.

The aluminosilicate particles have a mean particle size of about 80 nm.

The resin composite, in the cured form, has a flexural strength of atleast 100 MPa.

The ground structural filler contains less than 10% by volume ofparticles above 0.8 .mu.m in diameter.

The non-ground nanofiller has a refractive index in the range of about1.48 to about 1.6.

A topical composition may include a polymerizable compound, apolymerization initiator system, bridged polycyclic compounds, orcombinations thereof. These compositions may be suitable for restoringthe functionality and anatomy of a damaged tooth. Uses may include, butare not limited to, use as adhesives, surface sealants, liners,varnishes, and composite restoratives. Uses may include, but are notlimited to, impression materials, coatings for impression trays, andimpression systems. In some embodiments, topical compositions may impartantimicrobial activity to a contacted foot structure and/or surroundingtissue.

In some embodiments, a composition may include a polymer, a polymer mayinclude a poly vinyl, a poly vinyl acetate-copolymer, poly(vinylacetate-co-acid), latex, an acrylate, an methacrylate, cyanoacrylate, aresin, a light cured resin, a self-cured resin, a cement, a glassionomer cement (GIC), a polyurethane resin, or a bisphenol A glycidyl(bis-GMA) resin,

The present topical compositions may include a polymerizable compoundincluding, but not limited to, polymerizable amides, esters, alkenes,imides, acrylates, methacrylates, urethanes, vinyl esters or epoxy-basedmaterials. Other polymerizable compounds may include those based onstyrene, styrene acrylonitrilic, sulfones, acetals, carbonates,phenylene ethers, phenylene sulfides, or other polymerizable unitslisted herein.

Polymerizable compounds may include ethylenically unsaturated monomersand prepolymers and include those based on acrylic and methacrylicmonomers, for example those disclosed in U.S. Pat. Nos. 3,066,112,3,179,623, and 3,194,784 to Bowen; U.S. Pat. Nos. 3,751,399 and3,926,906 to Lee et al.; and commonly assigned U.S. Pat. No. 5,276,068to Wakline, which are incorporated by reference as if fully set forthherein. Methacrylate-based monomers may be used (e.g., condensationproduct of bisphenol A and glycidyl methacrylate,2,2′-bis[4-(3-methacryloxy-2-hydroxy propoxy)phenyl]-propane(“BIS-GMA”), dipentaerythritol pentaacrylate (DPEPA), pentaerythritoldimethacrylate (PEDM), the condensation product of ethoxylated bisphenolA and glycidyl methacrylate (“EBPA-DMA”), and the condensation productof 2 parts hydroxymethylmethacrylate and 1 part triethylene glycolbis(chloroformate) (“PCDMA”)). Polymerizable compounds may includepolyurethane-based dimethacrylates (“PUDMA”).

Polymerizable compounds may include polymerizable diluent monomers. Suchmonomers are generally used to adjust the viscosity of a polymerizablecomposition. Suitable methacrylate-based diluent monomers may include,but are not limited to, hydroxyalkyl methacrylates (e.g., 2-hydroxyethylmethacrylate, 1,6-hexanediol dimethacrylate, and 2-hydroxypropylmethacrylate); glyceryl dimethacrylate; and ethyleneglycol methacrylates(e.g., ethyleneglycol methacrylate, diethyleneglycol methacrylate,triethyleneglycol methacrylate, Triethyleneglycol dimethacrylate, andtetraethyleneglycol methacrylate).

When used as primers, adhesives, or primer/adhesive, topicalcompositions may include a polymerizable compound including hydrophilicpolymerizable monomers to enhance the bonding characteristics of thetopical composition. Topical compositions may be used as an adhesive,for example, in combination with a bandage wrap or a cast. Suitablepolymerizable hydrophilic monomers may have carboxyl, phosphoryl,sulfonyl, and/or hydroxyl functional groups. Examples of polymerizablehydrophilic monomers having at least one carboxyl group may include, butare not limited to, methacrylic acid, maleic acid p-vinylbenzoic acid,11-methacryloyloxy-1,1-undecanedicarboxylic acid,1,4-dimethacryloyloxyethylpyromellitic acid,6-methacryloyloxyethylnaphthalene-1,2,6-tricarboxylic acid,4-methacryloyloxymethyltrimellitic acid and the anhydride thereof,4-methacryloyloxyethyltrimellitic acid (“4-MET”) and an anhydridethereof (“4-META”), 4-(2-hydroxy-3-methacryloyloxy) butyltrimelliticacid and an anhydride thereof, 2,3-bis(3,4-dicarboxybenzoyloxy)propylmethacrylate, methacryloyloxytyrosine, N-methacryloyloxytyrosine,N-methacryloyloxyphenylalanine, methacryloyl-p-aminobenzoic acid, anadduct of 2-hydroxyethyl methacrylate with pyromellitic dianhydride(PMDM), and an adduct of 2-hydroxyethyl methacrylate with3,3′,4,4′-benzophenonetetracarboxylic dianhydride (BTDA) or3,3′,4,4′-biphenyltetracarboxylic dianhydride. Hydrophilic monomers mayinclude BPDM, the reaction product of an aromatic dianhydride with anexcess of 2-HEMA (2-hydroxyethyl methacrylate), as disclosed in U.S.Pat. No. 5,348,988, which are incorporated by reference as if fully setforth herein. Other hydrophilic monomers may include EDMT, the reactionproduct of 2-hydroxyethyl methacrylate (“2-HEMA”) with ethylene glycolbistrimellitate dianhydride; DSDM, the reaction product of3,3′,4,4′-diphenylsulfone tetracarboxylic dianhydride and 2-HEMA; PMDM,and PMGDM, the adduct of pyromellitic dianhydride with glyceroldimethacrylate.

Examples of polymerizable compounds having at least one phosphoric acidgroup may include, but are not limited to 2-methacryloyloxyethylacidophosphate, 2-methacryloyloxypropyl acidophosphate,4-methacryloyloxybutyl acidophosphate, 8-methacryloyloxyoctylacidophosphate, 10-methacryloyloxydecyl acidophosphate,bis(2-methacryloyloxyethyl)acidophosphate, and 2methacryloyloxyethylphenyl acidophosphate. The phosphoric acid group inthese compounds may be replaced with a thiophosphoric acid group.Examples of polymerizable compounds may include2-methacryloyloxyethylphenyl acidophosphate and 10-methacryloyloxydecylacidophosphate. Examples of polymerizable monomers having at least onesulfonic acid group include 2-sulfoethyl methacrylate, 3-sulfo-2-butylmethacrylate, 3-bromo-2-sulfo-2-propyl methacrylate,3-methoxy-1-sulfo-2-propyl methacrylate, and 1,1-dimethyl-2-sulfoethylmethacrylamide.

All the above polymerizable monomers may be used alone or incombination. All of the above polymerizable compounds may be firstpolymerized and then added to a composition as a polymer. Polymers maybe purchased. In some embodiments, a polymer may be combined with abridged polycyclic compound to form a composition. Polymers may furtherpolymerize during a curing process after a composition has been appliedto an surface. In some embodiments, a polymer, added to a composition,may include poly(vinyl acetate-co-crotonic acid). A composition mayinclude a prepolymer and/or a polymer capable of forming a film. Acomposition may include one or more solvents. Solvents may includeenvironmentally green solvents (e.g., water, alcohol (e.g., ethanol).Solvents may be applied to a surface as part of a composition. At leastsome of the solvents may evaporate as the composition forms a film overthe surface to which the composition was applied.

A topical composition may include a polymerization initiator system,including light curing, self-curing, dual curing, and vacuum, heat, andpressure curing systems as well as any combination thereof. Visiblelight curing systems employ light-sensitive compounds (e.g., benzildiketones and DL-camphorquinone) in amounts ranging from about 0.05 to0.5 weight percent. Visible light curing systems may includepolymerization accelerators (e.g., various organic tertiary amines wellknown in the art). In visible light curable compositions, the tertiaryamines are generally acrylate derivatives such as dimethylaminoethylmethacrylate and, particularly, diethylaminoethyl methacrylate (“DEAME”)in amounts in the range from about 0.05 to 0.5 weight percent.

Self-curing compositions may contain free radical polymerizationinitiators such as, for example, peroxides in amounts ranging from about2 to 6 weight percent. Suitable free radical initiators may includelauryl peroxide, tributyl hydroperoxide, cumene hydroperoxide, andbenzoyl peroxide. The heat and pressure curable systems also includeheat cure initiators such as aromatic sulfinic acids and salts thereof,benzoyl peroxide, 1,1′-azobis (cyclohexanecarbonitrile), or other freeradical initiators. Polymerization accelerators commonly used with theseinclude tertiary amines, generally aromatic tertiary amines such asethyl 4-(N,N-dimethyl)aminobenzoate (“EDAB”), dimethyl-p-toluidine,dihydroxyethyl-p-toluidine and the like, in amounts ranging from about0.05 to about 4.0 weight percent.

The topical restorative compositions may also comprise other additivesand solvents known in the art, for example, ultraviolet light absorbers,anti-oxidants such as BHT, stabilizers, fillers, pigments, opacifiers,handling agents, and others. An ultraviolet absorber may be employed inamounts ranging from about 0.05 to about 5.0 weight percent. Suchultraviolet absorbers may be desirable in the visible light curablecompositions in order to avoid discoloration of the resin from anyincident ultraviolet light. Suitable ultraviolet absorbers may includegelators, various benzophenones, particularly UV-9 and UV-5411 availablefrom American Cyanamid Company, and benzotriazoles known in the art,particularly 2-(2′-hydroxy-5′-methylphenyl)-benzotriazole, sold underthe trademark TINUVIN P by Ciba-Geigy Corporation, Ardsley, N.Y.

Fillers, such as colloidal silica, barium glasses, fibrous fillers,quartz, ceramic fillers and the like may also be incorporated intotopical compositions, particularly when they are to be used as bondingagents or filling composites. Suitable fillers may include fillersconventionally used in the topical industry capable of being covalentlybonded to the resin matrix itself or to a coupling agent which iscovalently bonded to both. Silane coupling agents are known, for examplemethacryloxypropyl trimethoxy silane. Such fillers are described in U.S.Pat. Nos. 4,544,359 and 4,547,531, which is incorporated by reference asif fully set forth herein. Examples of suitable filling materials mayinclude, but are not limited to, amorphous silica, spherical silica,colloidal silica, barium glasses, quartz, ceramic fillers, silicateglass, hydroxyapatite, calcium carbonate, fluoroaluminosilicate, bariumsulfate, quartz, barium silicate, strontium silicate, bariumborosilicate, barium boroaluminosilicate, strontium borosilicate,strontium boroaluminosilicate, glass fibers, lithium silicate,ammoniated calcium phosphate, deammoniated calcium phosphate, alumina,zirconia, tin oxide, polymer powders, polymethyl methacrylate,polystyrene, and polyvinyl chloride, titania, and combinations thereof.

Antimicrobials may be generally effective against organisms which causesecondary infection, and must not adversely affect the required physicalproperties of the cured compositions, in particular water sorption,diametral tensile strength, and hardness. In particular, the ADAspecification No. 27 requires topical resin composites to have watersorption values below 50 μg/mm³/week.

EXAMPLES

Having now described the invention, the same will be more readilyunderstood through reference to the following example(s), which areprovided by way of illustration, and are not intended to be limiting ofthe present invention.

General Experimental: All manipulations were carried out using Schlenktechnique. Concentrated hydrochloric acid and acetic acid were purchasedfrom J. T. Baker and used as received. Sodium hydroxide was purchasedfrom Mallinckrodt and used as received. Sodium dicyanamide and sodiumbicarbonate were purchased from Aldrich and used as received.Tris(2-aminoethyl)amine was purchased from Acros Organics and distilledbefore use. Terephthaldicarboxaldehyde and p-chloroaniline werepurchased from Aldrich and sublimed before use. Sodium sulfate waspurchased from EMD and used as received. Water was sparged for >10minutes before use. Dichloromethane, ethyl acetate and hexanes werepurchased from EMD and used as received. Ethyl alcohol, anhydrous 200proof, was purchased from Aldrich and used as received. Silica gel 60(230-400 mesh) was purchased from EMD and used as received. MS analysiswas performed on an Applied Biosystems Voyager DE instrument at HTLaboratories in San Diego, Calif. NMR analysis was performed on a JEOLEclipse⁺ 400 instrument at Acorn NMR, Inc. in Livermore, Calif.

Synthesis of 2: To a 12 L round bottom flask equipped with a refluxcondenser and addition funnel was added methanol (8 L) followed byterephthaldicarboxaldehyde (64.4 g, 0.480 moles). The solution washeated to 65° C. and tris(2-aminoethyl)amine (46.8 g, 47.9 mL, 0.320moles) was added. Then the solution was refluxed for about 16 h andcooled to room temperature. The solution was filtered to another 12 Lround bottom flask equipped with a reflux condenser and sodiumborohydride (60.5 g, 1.60 moles) was added. The solution was refluxedfor about 16 h and cooled to room temperature. The volatiles wereremoved by rotational evaporator and the residue dissolved indichloromethane (720 mL) and hydrochloric acid, 1.0 M (3.2 L). It wasstirred for 5 minutes. Then to the solution was added sodium hydroxide,3.0 M (1.6 L), the solution stirred for 5 minutes and the phasesseparated. The aqueous was extracted with dichloromethane (2×400 mL,2×200 mL), the organic phase combined, washed with water (2×600 mL) anddried over sodium sulfate. Then the volatiles were removed by vacuumtransfer to leave a slightly off white powder (89.6 g, 150 mmoles, 93.5%yield). Analysis of 2: ¹H NMR (400 MHz, CD₂Cl₂, δ): 2.61, 2.76 (m, 24H,NCH₂CH₂NHCH₂C₆H₄), 3.62 (s, 12H, NCH₂CH₂NHCH₂C₆H₄), 6.84 (s, 12H,NCH₂CH₂NHCH₂C₆H₄). ESI-MS (m/z): [M+H]⁺ 599, [M+H]²⁺ 300.

Synthesis of 3: Octa-amine 2 (19.9 g, 33.3 mmoles) was added to a 2 Lflask and combined with ethyl acetate (924 mL) and acetic acid (38.1 mL,40.0 g, 666 mmoles). The solution was filtered and hexanes (629 mL) wasadded which caused the product to crystallize. The solution was filteredand the precipitate washed with 80% hexanes, 20% ethyl acetate (1500mL). The product was transferred to a flask and the volatiles removed byvacuum transfer. The supernatant was combined with hexanes (300 mL),filtered and washed with of 80% hexanes, 20% ethyl acetate (1500 mL).The precipitate was transferred to a flask and the volatiles removed byvacuum transfer. To the supernatant was added the wash solution from thesecond crop which precipitated the third crop of product. The solutionwas filtered and washed with 80% hexanes, 20% ethyl acetate (1500 mL).The precipitate was transferred to a flask and the volatiles removed byvacuum transfer. The product is a slightly off white powder (33.7 g,31.3 mmoles, 93.9% yield). Alternatively, 2 is suspended in ethylalcohol followed by the slow addition of 20 equiv of glacial acetic acidfollowed by stirring; the solvent and excess acid are removed via rotaryevaporation and or a schenk line under vacuum resulting in 3. Analysisof 3: ¹H NMR (400 MHz, Methanol-d₄, δ): 1.88 (s, 24H, CH₃CO₂), 2.78,3.24 (m, 24H, CH₂CH₂), 4.14 (s, 12H, NCH₂Ph), 7.47 (s, 12H, Ph).MALDI-MS (m/z): [M]⁺ 600, [M+Na]⁺ 622.

Synthesis of 4: The compound p-chloroaniline (170 g, 1.33 moles) wasadded to a 1 L flask and dissolved in water (625 mL) and concentratedHCl (111 mL, 1.33 moles). Then in a separate 5 L flask sodiumdicyanamide (237 g, 2.66 moles) was dissolved in water (2035 mL) andheated to 50° C. The solution of p-chloroaniline was added to thesolution of sodium dicyanamide over 120 minutes, the flask was fittedwith a reflux condenser and then the reaction solution was heated forabout 16 h at 90° C. Then the reaction solution was allowed to cool andsaturated sodium bicarbonate (1500 mL) was added and the solutionstirred for 15 minutes. Ethyl acetate (1000 mL) was added and thesolution stirred for 10 minutes before the phases were separated. Theaqueous phase was extracted with ethyl acetate (10×1000 mL, 500 mL), theorganic was combined and washed with saturated brine (3×1200 mL), driedover sodium sulfate (anhydrous) and filtered. A 10 cm deep silica plugwas packed with silica/ethyl acetate slurry and then washed with ethylacetate (2000 mL). The product was sent through the silica plug and theplug washed with ethyl acetate (6000 mL). The volatiles were removedfrom the filtrate by vacuum transfer until about 10% of the solutionremained and the solution was filtered. The product was dried undervacuum to p<20 mtorr to leave a white powder. Then the product wasplaced under vacuum again at p<20 mtorr while on a 70° C. oil bath for18 h (203 g, 1.04 moles, 78.3% yield). Analysis of 4: ¹H NMR (400 MHz,DMSO-d₆, δ): 7.08 (s, 2H, PhNHC(NH)NHCN), 7.36 (m, 4H, Ph), 9.15 (s, 1H,PhNHC(NH)NHCN). MALDI-MS (m/z): [M]⁺ 195, [M+Na]⁺ 218.

Synthesis of compound 4 has been described in patent GB599722 and J.Chem. Soc. 1946, p 729-737 and 1948, p 1630-1636, which are incorporatedby reference as if fully set forth herein. Synthesis of compoundssimilar to compound 4 are described in U.S. Pat. Nos. 2,455,807 and5,534,565, which are incorporated by reference as if fully set forthherein.

Synthesis of 5: Intermediate 3 (32.9 g, 30.5 mmoles) was added to a 500mL flask followed by 1-butanol (30.3 mL) which formed a slurry. Then 4(39.1 g, 201 mmoles) was added. The flask was fitted with a refluxcondenser and placed into an oil bath set to reach 90° C. It was heatedfor 3 days and allowed to cool to room temperature. The volatiles wereremoved by vacuum transfer and the resulting foam was crushed to apowder. The crude product was dissolved in ethyl alcohol (31.9 mL) andethyl acetate (65.4 mL). The product was precipitated with ethyl acetate(915 mL) and the solution filtered. Then the product was washed withethyl acetate (980 mL) and the volatiles removed by vacuum transfer toproduce a white powder (57.9 g, 25.8 mmoles, 84.5% yield).Alternatively, the resulting crude product 5 foam was crushed to apowder and dissolved in water followed by extraction of the aqueousphase 3 times with ethyl acetate resulting in an off white powder 5 in˜77% yield. Analysis of 5: MALDI-MS (m/z): 1269 [M+5 DHB]²⁺, 1423 [M+7DHB]²⁺ (DHB is MALDI matrix dihydroxybenzoic acid).

The product 5 can be converted to the freebase and then protonated withmineral, organic or other acids to afford the desired counter ion(anion) (for example 5 can be treated with base, isolated as thefreebase and treated with acetic acid to regenerate 5, i.e. replaceacetic acid with a different acid such as D-Gluconic Acid, Butyric Acid,Nalidixic Acid, Statin Acids (e.g., pravastatin, fluvastatin,atorvastatin, etc.), Nicotinic Acid (i.e. Niacin), Enrofloxacin (orcombination of acids) to generate the salt containing the desired anioncounter-ion and/or mixture). Analysis of Freebase of 5: MALDI-MS (m/z):883 [M]²⁺

Combining of the Freebase of 5 and Nalidixic Acid

To a vial and stirbar, (0.026 mg, 0.015 mmol) of the freebase of 5 wasadded followed by 2.0 mL of acetone, 1.0 mL of deionized water and 8equiv. (0.028 g, 0.12 mmol) of Nalidixic acid. The mixture was stirredfor about 1 h to form a clear homogeneous solution. MALDI-MS (m/z): 1210[M]³⁺[M]²⁺ −1 Nalidixic Acid 1697; [M]²⁺ −2 Nalidixic Acid 1580.

Combining of the Freebase of 5 and Enrofloxacin

To a vial and stirbar, (0.027 mg, 0.015 mmol) of the freebase of 5 wasadded followed by 2.0 mL of acetone and 1.0 mL of deionized water and 8equiv. (0.027 mg, 0.015 mmol) of Enrofloxacin. The mixture was stirredfor about 1 h to form a clear homogeneous solution.

Example of an Otic Composition Formulation with Glycerol

To a vial and stirbar, (0.050 g, 0.022 mmol) 5 was added followed by0.95 g of glycerol. The mixture was stirred and heated to 40° C. for 5min. resulting in a clear homogeneous solution.

Example of an Otic Composition Formulation with Water

To a vial and stirbar, (0.050 g, 0.022 mmol) 5 was added followed by0.95 g of deionized water. The mixture was stirred at room temperatureand/or optionally heated to 40° C. for 5 min. resulting in a clearhomogeneous solution.

Formulation of Topical Sealant

General: Poly(vinyl acetate-co-crotonic acid) beads and ethyl alcohol(anhydrous 200 proof) were purchased from Aldrich and used withoutfurther purification.

Example: Poly(vinyl acetate-co-crotonic acid) (0.80 g) was dissolved inwater (1.74 mL) and ethyl alcohol (7.81 mL). Compound 5 (0.50 g) wasdissolved in ethyl alcohol (1.00 mL). The two solutions were combinedand mixed for 2 hours.

Formulation of Topical Composition

Example: The active ingredient 5 was dissolved in ethyl alcohol and/orwater.

Other common topical formulation or coating formulation components knownby those skilled in the art may be used in conjunction with or in placeof the above example.

In this patent, certain U.S. patents, U.S. patent applications, andother materials (e.g., articles) have been incorporated by reference.The text of such U.S. patents, U.S. patent applications, and othermaterials is, however, only incorporated by reference to the extent thatno conflict exists between such text and the other statements anddrawings set forth herein. In the event of such conflict, then any suchconflicting text in such incorporated by reference U.S. patents, U.S.patent applications, and other materials is specifically notincorporated by reference in this patent.

Further modifications and alternative embodiments of various aspects ofthe invention will be apparent to those skilled in the art in view ofthis description. Accordingly, this description is to be construed asillustrative only and is for the purpose of teaching those skilled inthe art the general manner of carrying out the invention. It is to beunderstood that the forms of the invention shown and described hereinare to be taken as the presently preferred embodiments. Elements andmaterials may be substituted for those illustrated and described herein,parts and processes may be reversed, and certain features of theinvention may be utilized independently, all as would be apparent to oneskilled in the art after having the benefit of this description of theinvention. Changes may be made in the elements described herein withoutdeparting from the spirit and scope of the invention as described in thefollowing claims.

What is claimed is:
 1. A method of coating an animal topical surface, comprising: applying a chemical compound to at least a portion of an animal topical surface, the chemical compound comprising a bridged polycyclic compound having a structure (Ib):

wherein Z comprises at least one bridge, wherein at least one of the bridges is —R²—N⁺R³ ₂—R⁴—N⁺R³ ₂—R²—, —R²—NR³—R⁴—N⁺R³ ₂—R²—, or —R²—NR³—R⁴—NR³—R²—, and wherein each bridge independently couples R¹ to R¹; wherein each bridge independently couples R¹ to R¹; wherein each R¹ is independently N, N⁺H, or N⁺R³; wherein each R² is independently an alkyl group, a substituted alkyl group, or an alkene; wherein each R³ is independently a pharmaceutically active agent, a hydrogen, an ester, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, a heterocycle group, a substituted heterocycle group, an alkene, an ether, a guanidine derivative, a polyethyleneglycol, a polyethyleneimine, or any combination of these, and wherein at least two R³s are a pharmaceutically active agent comprising a guanidine or a guanidine derivative; wherein each R⁴ is independently an aryl group or a substituted aryl group; wherein when R⁴ is an aryl group the aryl group is a phenyl, a naphthyl, a biphenyl, a diphenylmethyl, or a benzophenone; and wherein when R⁴ is a substituted aryl group the substituted aryl group is a phenyl having at least one substituent, a naphthyl having at least one substituent, a biphenyl having at least one substituent, a diphenylmethyl having at least one substituent, or a benzophenone having at least one substituent, wherein when R⁴ is a substituted aryl group the substituted aryl group of R⁴ has at least two substituents and each of two of the substituents of the substituted aryl group of R⁴ are independently coupled to the adjacent nitrogen of the —NR³—R² moiety or the —N⁺R³ ₂—R²— moiety of the structure (Ib) or when R⁴ is a substituted aryl group the substituted aryl group of R⁴ has at least one substituent such that at least two moieties forming an aryl group of the substituted aryl group of R⁴ are independently coupled to the adjacent nitrogen of the —NR³—R²— moiety or the —N⁺R³ ₂—R²— moiety of the structure (Ib); forming a coating over at least a portion of the animal topical surface; inhibiting or ameliorating at least one malady associated with an animal topical surface and/or tissue associated with an animal topical surface; and wherein at least one of the maladies is pyoderma, bacterial dermatitis, interdigital furunculosis, an infection, or a parasite.
 2. The method of claim 1, wherein at least two cyclic groups are defined in part by quaternary ammonium moieties.
 3. The method of claim 1, wherein Y is a halogen, an alcohol, or a pharmaceutical active agent; wherein X is a counterion; wherein n ranges from 1-10, 2-8, 2-4, 3-6, 2-3, or 1-3; wherein each z is independently a charge on the bridged polycyclic compound and an appropriate number of counterions, wherein z ranges from 1-16, 2-14, 6-14, 8-14, or 12-20; and wherein Z comprises at least one bridge, wherein at least one of the bridges is


4. The method of claim 1, wherein one or more of the bridged polycyclic compounds is a salt of the bridged polycyclic compound, and wherein at least one counterion forming the salt is an acetate ion.
 5. The method of claim 1, wherein the chemical compound is part of a chemical composition, and wherein the chemical composition comprises a polymer or a prepolymer.
 6. The method of claim 1, wherein the chemical compound is part of a chemical composition, and wherein the chemical composition comprises a polymer or a prepolymer, wherein at least one polymer is poly(vinyl acetate-co-crotonic acid).
 7. The method of claim 1, wherein the chemical compound is part of a chemical composition, and wherein the chemical composition comprises an alcohol based solvent, wherein at least one alcohol based solvent is ethanol.
 8. The method of claim 1, wherein the chemical compound is part of a chemical composition, and wherein the chemical composition comprises a pharmaceutically acceptable viscous liquid.
 9. The method of claim 1, wherein at least one of the pharmaceutically active agents is an antiviral agent, an anti-inflammatory agent, and/or an antimicrobial agent.
 10. The method of claim 1, wherein at least one of the pharmaceutically active agents is an antigen blocker or inhibitor.
 11. The method of claim 1, wherein at least one of the pharmaceutically active agents is an allergen blocker or inhibitor.
 12. The method of claim 1, wherein the animal topical surface comprises at least a portion of a foot surface, at least a portion of a hoof, at least a portion of soft tissue, at least a portion of a surgical site, and/or at least a portion of a suture site.
 13. The method of claim 1, wherein the malady is a wound, a cut, a sore, and/or a scrape.
 14. The method of claim 1, wherein, the animal is a canine and/or a feline.
 15. The method of claim 1, wherein the animal is a cow, a goat, a sheep, a rabbit, a swine, a deer, a guinea pig, a turkey, an ostrich, an avian, a reptile, a ferret, a horse, a tiger, a lion, and/or a chicken.
 16. A method of inhibiting or ameliorating a malady associated with an otic cavity, comprising: applying a chemical compound to at least a portion of a surface associated with an otic cavity, the chemical compound comprising a bridged polycyclic compound having a structure (Ib):

wherein Z comprises at least one bridge, wherein at least one of the bridges is —R²—N⁺R³ ₂—R⁴—N⁺R³ ₂—R²—, —R²—NR³—R⁴—N⁺R³ ₂—R²—, or —R²—NR³—R⁴—NR³—R²—, and wherein each bridge independently couples R¹ to R¹; wherein each R¹ is independently N, N⁺H, or N⁺R³; wherein each R² is independently an alkyl group, a substituted alkyl group, or an alkene; wherein each R³ is independently a pharmaceutically active agent, a hydrogen, an ester, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, a heterocycle group, a substituted heterocycle group, an alkene, an ether, a guanidine derivative, a polyethyleneglycol, a polyethyleneimine, or any combination of these, and wherein at least two R³s are a pharmaceutically active agent comprising a guanidine or a guanidine derivative; and wherein each R⁴ is independently an aryl group or a substituted aryl group; wherein when R⁴ is an aryl group the aryl group is a phenyl, a naphthyl, a biphenyl, a diphenylmethyl, or a benzophenone; wherein when R⁴ is a substituted aryl group the substituted aryl group is a phenyl having at least one substituent, a naphthyl having at least one substituent, a biphenyl having at least one substituent, a diphenylmethyl having at least one substituent, or a benzophenone having at least one substituent, wherein when R⁴ is a substituted aryl group the substituted aryl group of R⁴ has at least two substituents and each of two of the substituents of the substituted aryl group of R⁴ are independently coupled to the adjacent nitrogen of the —NR³—R²— moiety or the —N⁺R³ ₂—R²— moiety of the structure (Ib) or when R⁴ is a substituted aryl group the substituted aryl group of R⁴ has at least one substituent such that at least two moieties forming an aryl group of the substituted aryl group of R⁴ are independently coupled to the adjacent nitrogen of the —NR³—R²— moiety or the —N⁺R³ ₂—R²— moiety of the structure (Ib); forming a coating over at least a portion of the surface; and inhibiting and/or ameliorating at least one malady associated with an otic cavity and/or tissue associated with a otic cavity.
 17. The method of claim 1, wherein a substituted aryl group comprises an alkyl-aryl group or a substituted alkyl-aryl group.
 18. The method of claim 1, wherein the chemical compound is part of a chemical composition, wherein the chemical composition further comprises glycerol or propylene glycol.
 19. The method of claim 16, wherein a substituted aryl group comprises an alkyl-aryl group or a substituted alkyl-aryl group.
 20. The method of claim 16, wherein the chemical compound is part of a chemical composition, wherein the chemical composition further comprises glycerol or propylene glycol. 